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Variant interpretation report

BMPR1A c.1299C>T, p.(Phe433=)

NM_004329.3:c.1299C>T NP_004320.2:p.(Phe433=) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About BMPR1A

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 4
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 4
BS1Strong
BS1 · strong

The variant has an allele frequency of 0.557% in the African/African American population (gnomAD v2.1) and a grpmax FAF of 0.478%, exceeding the BS1 threshold of >0.3% for a rare autosomal dominant disorder (juvenile polyposis syndrome, prevalence ~1/100,000). This frequency is incompatible with a highly penetrant pathogenic variant.

BS2Supporting
BS2 · supporting

This variant has been observed in the homozygous state in population databases (1 homozygote in gnomAD v2.1, 2 homozygotes in gnomAD v4.1). BMPR1A is associated with autosomal dominant juvenile polyposis syndrome, and homozygous observation in a population database is inconsistent with a highly penetrant pathogenic variant for a dominant disorder with expected early onset.

BP4Supporting
BP4 · supporting

SpliceAI predicts no splicing impact (max delta score = 0.00). This synonymous variant is not predicted to create or disrupt any splice site, supporting a benign interpretation.

BP6Supporting
BP6 · supporting

Thirteen clinical laboratories have independently classified this variant as Benign (9 labs including 8 as Benign and 1 as benign) or Likely benign (4 labs) in ClinVar (Variation ID 136525). This represents a strong consensus among clinical diagnostic laboratories that this variant is benign.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 strong benign, BS2 supporting benign, BP4 supporting benign, BP6 supporting benign; combination = 1 strong benign + 3 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
545 / 1,614,170 alleles

gnomAD v4.1: 545 / 1,614,170 alleles. Recorded AF 0.000337635. Recorded homozygote count 2.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000604458; MAF= 0.06045%, 171/282898 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00556713; MAF= 0.55671%, 139/24968 alleles, homozygotes = 1); grpmax FAF= 0.00478047.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0006514657980456026, 12/18420 alleles, homozygotes = 0).

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

ClinVar submissions
13 reported laboratory submissions

8 Benign · 4 Likely benign · 1 benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 4 met · 15 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Met Not met Not assessed Not applicable

NM_004329.3:c.1299C>T (p.Phe433=) is a synonymous variant in BMPR1A with an allele frequency of 0.557% in the African/African American population (gnomAD v2.1, grpmax FAF 0.48%), exceeding the expected frequency for juvenile polyposis syndrome.

The variant has been observed in the homozygous state in population databases (1 homozygote in gnomAD v2.1; 2 homozygotes in gnomAD v4.1), which is inconsistent with a highly penetrant autosomal dominant disorder.

SpliceAI predicts no splicing impact (max delta score = 0.00), consistent with a benign synonymous variant.

Thirteen clinical diagnostic laboratories have independently classified this variant as Benign or Likely benign in ClinVar (Variation ID 136525).

Applying generic ACMG/AMP 2015 criteria: BS1 (strong benign), BS2 (supporting benign), BP4 (supporting benign), and BP6 (supporting benign) are met. One strong benign plus three supporting benign criteria classifies this variant as Likely Benign.

Met · 4

BS1 StrongThe variant has an allele frequency of 0.557% in the African/African American population (gnomAD v2.1) and a grpmax FAF of 0.478%, exceeding the BS1 threshold of >0.3% for a rare autosomal dominant disorder (juvenile polyposis syndrome, prevalence ~1/100,000). This frequency is incompatible with a highly penetrant pathogenic variant. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 African AF = 0.557% (139/24
  • 968 alleles
  • 1 homozygote)
  • grpmax FAF = 0.478%. gnomAD v4.1 African AF = 0.525% (394/75
  • 032 alleles
  • 2 homozygotes)
  • grpmax FAF = 0.482%.
Sources
BS2 SupportingThis variant has been observed in the homozygous state in population databases (1 homozygote in gnomAD v2.1, 2 homozygotes in gnomAD v4.1). BMPR1A is associated with autosomal dominant juvenile polyposis syndrome, and homozygous observation in a population database is inconsistent with a highly penetrant pathogenic variant for a dominant disorder with expected early onset. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 1 homozygote (African
  • exome). gnomAD v4.1: 2 homozygotes (African). BMPR1A JPS is autosomal dominant with early-onset polyposis.
Sources
BP4 SupportingSpliceAI predicts no splicing impact (max delta score = 0.00). This synonymous variant is not predicted to create or disrupt any splice site, supporting a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00. No acceptor gain
  • acceptor loss
  • donor gain
  • or donor loss predicted.
Sources
BP6 SupportingThirteen clinical laboratories have independently classified this variant as Benign (9 labs including 8 as Benign and 1 as benign) or Likely benign (4 labs) in ClinVar (Variation ID 136525). This represents a strong consensus among clinical diagnostic laboratories that this variant is benign. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 136525: Benign by 8 clinical labs
  • Likely benign by 4 clinical labs
  • benign by 1 clinical lab. Total 13 labs converging on benign/likely benign.
Still missing
  • ClinVar review status is 'criteria provided
  • single submitter' (not expert panel consensus).
Sources

Not met · 15 · evaluated, threshold not reached

PS2 No de novo data available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in ClinVar submissions or literature.
Still missing
  • No family studies or de novo testing data available.
PS3 No functional data available for this synonymous variant. SpliceAI predicts no splice impact (max delta = 0.00). No experimental studies have tested this variant or a systematically characterized range that includes it. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00
  • no functional studies identified.
Still missing
  • No variant-specific functional studies available.
Sources
PS4 No case-control enrichment data available. The variant is observed in population databases at frequencies incompatible with a rare dominant disorder, suggesting it is unlikely to be enriched in affected individuals. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 171/282
  • 898 alleles (0.06%)
  • gnomAD v4.1: 545/1
  • 614
  • 170 alleles (0.034%). No case-control enrichment data.
Still missing
  • No case-control or cohort enrichment data.
Sources
PM1 This synonymous variant falls within the BMPR1A protein kinase domain (codons 206-493) but there is no evidence that this silent substitution has any functional consequence on the domain. SpliceAI max delta = 0.00 confirms no splice disruption. Domain location alone is insufficient for PM1 when the variant is synonymous and predicted to have no effect. Details ▾Hide ▴
Evidence considered
  • Variant at codon 433 falls within the protein kinase domain (206-493)
  • but synonymous change has no predicted effect
  • SpliceAI delta = 0.00.
Still missing
  • No functional evidence of domain disruption by this synonymous substitution.
Sources
PM2 The variant has grpmax filtering allele frequency of 0.478% in gnomAD v2.1 and 0.556% in the African population, exceeding the PM2 threshold of <0.1%. This variant is too common in population databases to apply PM2. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 grpmax FAF = 0.478%
  • African AF = 0.557%. gnomAD v4.1 grpmax FAF = 0.482%
  • African AF = 0.525%.
Sources
PM6 No de novo data available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • No family studies or de novo testing data.
PP1 No segregation data available for this variant. Details ▾Hide ▴
Evidence considered
  • No cosegregation studies identified.
Still missing
  • No family segregation data.
PP3 SpliceAI max delta = 0.00, and REVEL/BayesDel scores are not available. No in silico evidence of a deleterious effect is present. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00. REVEL/BayesDel not available for this variant.
Still missing
  • Conservation data (GERP/phyloP) not available to assess nucleotide-level constraint.
Sources
PP4 No patient phenotype or clinical data available for independent assessment. Details ▾Hide ▴
Evidence considered
  • No phenotype data or clinical case reports identified.
Still missing
  • No patient-specific clinical data available.
PP5 ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel). Per the PP5/BP6 rule, supporting strength is reserved for ClinVar 3-star EP classifications. ClinVar consensus is Benign/Likely benign, which is evidence against pathogenicity, not for it. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 136525: Benign (8 labs)
  • Likely benign (4 labs)
  • benign (1 lab). Review status: criteria provided
  • single submitter (not 3-star EP).
Sources
BA1 gnomAD overall allele frequency is 0.06% (v2.1) and 0.034% (v4.1), both below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 overall AF = 0.06%
  • gnomAD v4.1 overall AF = 0.034%. Both below BA1 >1% threshold.
Sources
BS3 No well-established functional studies demonstrating no deleterious effect are available for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies demonstrating a benign effect identified.
Still missing
  • No experimental functional data available.
BS4 No segregation data demonstrating lack of cosegregation with disease is available. Details ▾Hide ▴
Evidence considered
  • No family segregation data identified.
Still missing
  • No cosegregation studies available.
BP2 No data available regarding observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
  • No trans-phase data available.
Still missing
  • No phase information with known pathogenic variants.
BP5 No data available regarding an alternate molecular basis for disease in an individual carrying this variant. Details ▾Hide ▴
Evidence considered
  • No cases with an alternate molecular diagnosis identified.
Still missing
  • No case-level data with alternate molecular diagnosis.

Not assessed · 1 · no assessment recorded

BP7 This is a synonymous variant (p.Phe433=) with SpliceAI max delta = 0.00, satisfying two of three BP7 requirements. However, conservation data (GERP/phyloP) for nucleotide c.1299 is not available, and the nucleotide cannot be confirmed as not highly conserved. Phe433 is located within the protein kinase domain, a conserved region. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Phe433=)
  • SpliceAI max delta = 0.00. Conservation data not available.
Still missing
  • Nucleotide-level conservation data (GERP/phyloP) needed to confirm the nucleotide is not highly conserved.
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004329.3:c.1299C>T is a synonymous variant (p.Phe433=) and does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Details ▾Hide ▴
Evidence considered
  • Synonymous variant with no predicted protein truncation or splice disruption.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/APS1 requires a different nucleotide change at the same position that produces the same amino acid change. This is a synonymous variant (p.Phe433=) with no amino acid change. Details ▾Hide ▴
Evidence considered
  • Synonymous variant with no amino acid change
  • PS1 semantics do not apply.
PM5 N/APM5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been seen. This is a synonymous variant (p.Phe433=) with no amino acid change. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • no amino acid residue altered
  • PM5 semantics do not apply.
Sources
pm5_candidates
PP2 N/APP2 is specific to missense variants in genes with a low rate of benign missense variation. This is a synonymous variant (p.Phe433=), not a missense variant. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • PP2 applies to missense variants only.
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a synonymous variant (p.Phe433=), not a missense variant. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • BP1 applies to missense variants only.
BP3 N/ABP3 applies to in-frame indels in repetitive regions; this is a single nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 requires a different nucleotide change at the same position associated with a pathogenic amino acid change. This is a synonymous variant with no amino acid change; PS5 semantics do not apply. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • no comparator pathogenic nucleotide change at c.1299 identified.

Identifiers

Gene
BMPR1A
Transcript
NM_004329.3
Coding (HGVS c.)
NM_004329.3:c.1299C>T
Protein (HGVS p.)
NP_004320.2:p.(Phe433=)
GRCh38
chr10:86921652 C>T
GRCh37
chr10:88681409 C>T
ClinVar
136525

Gene diagram

Every interpreted variant in BMPR1A, mapped onto the exon structure of NM_004329.3. Select a row to find it on the plot.

BMPR1ANM_004329.3
Fetching transcript structure from UCSC…
gnomAD v4.1 545 / 1,614,170 alleles AF 0.000338 · 2 homozygotes · FAF 0.00482
gnomAD v2.1 171 / 282,898 alleles AF 0.000604 · 1 homozygotes · FAF 0.00478
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00034 · 545 / 1,614,170 alleles · 2 hom · FAF 0.0048
African/African American394 / 75,032 0.00532 hom
Remaining individuals54 / 62,510 0.00086
Admixed American46 / 60,020 0.00077
Middle Eastern3 / 6,062 0.00049
East Asian3 / 44,886 6.7e-05
South Asian4 / 91,080 4.4e-05
European (non-Finnish)41 / 1,180,028 3.5e-05
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, Ashkenazi Jewish.

gnomAD v2.1

AF 0.0006 · 171 / 282,898 alleles · 1 hom · FAF 0.0048
African/African American139 / 24,968 0.00561 hom
Admixed American25 / 35,440 0.00071
East Asian1 / 19,954 5e-05
European (non-Finnish)5 / 129,200 3.9e-05
South Asian1 / 30,616 3.3e-05
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, European (Finnish), Remaining individuals.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000337635; MAF= 0.03376%, 545/1614170 alleles, homozygotes = 2) and has highest observed frequency in the African/African American population (AF= 0.00525109; MAF= 0.52511%, 394/75032 alleles, homozygotes = 2); grpmax FAF= 0.00482358.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000604458; MAF= 0.06045%, 171/282898 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00556713; MAF= 0.55671%, 139/24968 alleles, homozygotes = 1); grpmax FAF= 0.00478047.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0006514657980456026, 12/18420 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingSpliceAI predicts no splicing impact (max delta score = 0.00). This synonymous variant is not predicted to create or disrupt any splice site, supporting a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00. No acceptor gain
  • acceptor loss
  • donor gain
  • or donor loss predicted.
Sources
PP3 SpliceAI max delta = 0.00, and REVEL/BayesDel scores are not available. No in silico evidence of a deleterious effect is present. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00. REVEL/BayesDel not available for this variant.
Still missing
  • Conservation data (GERP/phyloP) not available to assess nucleotide-level constraint.
Sources
BP7 This is a synonymous variant (p.Phe433=) with SpliceAI max delta = 0.00, satisfying two of three BP7 requirements. However, conservation data (GERP/phyloP) for nucleotide c.1299 is not available, and the nucleotide cannot be confirmed as not highly conserved. Phe433 is located within the protein kinase domain, a conserved region. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Phe433=)
  • SpliceAI max delta = 0.00. Conservation data not available.
Still missing
  • Nucleotide-level conservation data (GERP/phyloP) needed to confirm the nucleotide is not highly conserved.
Sources

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    Richards S et al. · 2015
    ACMG/AMP joint consensus guidelines for the interpretation of sequence variants. This methodology paper defines the criteria framework but does not discuss the BMPR1A c.1299C>T variant.
    Does not name this variant
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    Karbassi I et al. · 2016
    Describes a standardized DNA variant scoring system for pathogenicity assessments in Mendelian disorders. This methodology paper does not discuss the BMPR1A c.1299C>T variant.
    Does not name this variant
    PMID 26467025 ↗
  • Juvenile Polyposis Syndrome.
    Adam MP et al. · 1993
    GeneReviews summary of Juvenile Polyposis Syndrome, covering BMPR1A and SMAD4 gene-level information. The specific variant c.1299C>T is not discussed.
    Does not name this variant
    PMID 20301642 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. This is a clinical practice guideline and does not discuss the BMPR1A c.1299C>T variant.
    Does not name this variant
    PMID 25394175 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ Cancer Genetics Risk Assessment and Counseling summary. This is a health professional reference and does not discuss the BMPR1A c.1299C>T variant.
    Does not name this variant
    PMID 26389258 ↗
  • Genetics of Colorectal Cancer (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ Genetics of Colorectal Cancer summary. This is a health professional reference and does not discuss the BMPR1A c.1299C>T variant.
    Does not name this variant
    PMID 26389505 ↗
  • ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).
    Miller DT et al. · 2022
    ACMG SF v3.1 list for reporting of secondary findings. This policy statement lists genes recommended for secondary findings reporting but does not discuss the BMPR1A c.1299C>T variant.
    Does not name this variant
    PMID 35802134 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc comprehensive refinement of the ACMG-AMP variant classification criteria. This methodology paper does not discuss the BMPR1A c.1299C>T variant.
    Does not name this variant
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000337635; MAF= 0.03376%, 545/1614170 alleles, homozygotes = 2) and has highest observed frequency in the African/African American population (AF= 0.00525109; MAF= 0.52511%, 394/75032 alleles, homozygotes = 2); grpmax FAF= 0.00482358.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000604458; MAF= 0.06045%, 171/282898 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00556713; MAF= 0.55671%, 139/24968 alleles, homozygotes = 1); grpmax FAF= 0.00478047.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0006514657980456026, 12/18420 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Likely benign (4 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 136525)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.