About BMPR1A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BMPR1A c.398A>G, p.(Tyr133Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_004329.3:c.398A>G is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the PM2 criterion for a variant with allele frequency below 0.1% in large population cohorts.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BMPR1A, a transmembrane receptor kinase, is frequently altered by mutation and deletion in various cancers, including colorectal and endometrial cance
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.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 12 not met · 9 not assessed · 4 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.398A>G (p.Tyr133Cys) is a missense variant in exon 6 of BMPR1A, a gene in which pathogenic variants cause juvenile polyposis syndrome and are associated with hereditary colorectal cancer.
This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2 (supporting) for rarity.
REVEL in silico prediction (0.623) is moderately elevated, but BayesDel (0.073) and SpliceAI (max delta 0.00) do not agree with a deleterious interpretation; PP3 is not met.
The ClinVar entry (Variation ID 824461) is classified as Uncertain Significance by a single clinical laboratory (Ambry Genetics); no reputable source has classified this variant as pathogenic or benign.
No functional studies, de novo reports, cosegregation data, or case-control studies were identified for this specific variant.
The only criterion met is PM2 (supporting); no pathogenic or benign criteria of higher strength are satisfied. Overall, the evidence is insufficient to classify this variant above or below VUS under the generic ACMG/AMP 2015 framework.
No criteria match.
Met · 1
PM2 SupportingNM_004329.3:c.398A>G is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the PM2 criterion for a variant with allele frequency below 0.1% in large population cohorts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (allele count 0)
- Absent from gnomAD v4.1 (allele count 0)
Sources
Not met · 12 · evaluated, threshold not reached
PS2 No de novo occurrence data are available for NM_004329.3:c.398A>G. Targeted literature and database searches did not identify any report of this variant arising de novo with confirmed parentage. Details ▾Hide ▴
Evidence considered
- Exploratory evidence search found no de novo reports for this variant
Still missing
- No parental testing data available
PS4 The variant is absent from gnomAD population databases, but no case-control study has demonstrated statistically significant enrichment of NM_004329.3:c.398A>G in affected individuals versus controls. The single ClinVar submission (Ambry Genetics, VUS) does not provide case-level prevalence data sufficient for PS4. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- ClinVar: single VUS submission
- no case-control data
Still missing
- No case-control association study for this variant in juvenile polyposis syndrome or colorectal cancer cohorts
Sources
PM5 No known pathogenic missense variant at the same amino acid residue (Tyr133) was identified in ClinVar. The automated PM5 candidate search returned zero comparator variants. PM5 cannot be applied without a qualifying comparator. Details ▾Hide ▴
Evidence considered
- Zero same-residue pathogenic missense comparator variants identified in ClinVar
Still missing
- No known pathogenic missense variants at residue 133
Sources
pm5_candidates
PM6 No evidence of assumed de novo occurrence is available. No parental testing data or de novo case report was identified for NM_004329.3:c.398A>G. Details ▾Hide ▴
Still missing
- No de novo reports or parental testing data
PP1 No cosegregation data are available for NM_004329.3:c.398A>G with disease in multiple affected family members. Targeted literature search identified no family studies reporting this variant. Details ▾Hide ▴
Still missing
- No family cosegregation studies available
PP3 REVEL score of 0.623 is moderately elevated above the 0.5 threshold, suggesting possible deleterious effect. However, BayesDel score of 0.073 does not reach the deleterious threshold (typically >0.13), and SpliceAI max delta score is 0.00, predicting no splice impact. Multiple lines of computational evidence do not reach consensus for a deleterious effect, which is required for PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.623 (>0.5 threshold
- suggesting deleterious)
- BayesDel: 0.073 (<0.13 threshold
- not supporting deleterious)
- SpliceAI: max delta 0.00 (no splice impact predicted)
Sources
PP5 The ClinVar entry for NM_004329.3:c.398A>G (Variation ID 824461) is classified as Uncertain Significance by a single clinical laboratory (Ambry Genetics). No reputable source has classified this variant as pathogenic. PMID:25394175 is a general practice guideline on cancer predisposition referral indications and does not report this specific variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- single submitter (Ambry Genetics)
- criteria provided
- PMID:25394175 is a practice guideline
- not a variant-specific report
Sources
clinvar ↗25394175
BA1 NM_004329.3:c.398A>G is absent from gnomAD v2.1 and v4.1, yielding an allele frequency of 0%, which is far below the >1% threshold required for BA1. Details ▾Hide ▴
BS1 The variant is absent from gnomAD v2.1 and v4.1, yielding an allele frequency of 0%, which is below the >0.3% threshold required for BS1. Details ▾Hide ▴
BP1 Missense variants are a recognized disease mechanism in BMPR1A. The gene context literature explicitly identifies non-truncating BMPR1A variants as associated with familial colorectal cancer and adenomatous polyps (PMID:41023686). Therefore, BP1, which applies only when truncating variants are the primary disease mechanism, is not met. Details ▾Hide ▴
Evidence considered
- Non-truncating BMPR1A variants are associated with familial colorectal cancer and adenomatous polyps (PMID:41023686)
Sources
41023686
BP4 REVEL score of 0.623 is above the 0.5 threshold, suggesting possible deleterious effect rather than neutral impact. BayesDel score of 0.073 and SpliceAI max delta of 0.00 do not provide consensus support for a benign prediction. Multiple lines of computational evidence do not converge on a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.623 (above 0.5 threshold
- not supporting benign)
- BayesDel: 0.073 (neutral to slightly benign)
- SpliceAI: max delta 0.00 (neutral)
Sources
BP6 The ClinVar classification for NM_004329.3:c.398A>G (Variation ID 824461) is Uncertain Significance from a single clinical laboratory. No reputable source has classified this variant as benign. Details ▾Hide ▴
Not assessed · 9 · no assessment recorded
PS1 No alternative nucleotide change at codon 133 producing the same amino acid change (p.Tyr133Cys) was identified as a known pathogenic variant. Insufficient data to apply PS1. Details ▾Hide ▴
Still missing
- No known pathogenic variant at codon 133 arising from a different nucleotide change
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect on BMPR1A function were identified for NM_004329.3:c.398A>G (p.Tyr133Cys). Details ▾Hide ▴
Still missing
- No functional study assessing the impact of p.Tyr133Cys on BMPR1A signaling
- protein expression
- or downstream pathway activation
PM1 Residue 133 is located in the extracellular ligand-binding domain of BMPR1A, but no VCEP-defined mutational hotspot or critical functional domain has been established for BMPR1A in the generic ACMG context. Cancer Hotspots analysis shows no statistical significance at this residue. Details ▾Hide ▴
Evidence considered
- Residue 133 is not a statistically significant hotspot per Cancer Hotspots
- No VCEP/ClinGen-defined PM1 domain exists for BMPR1A
Still missing
- No formal PM1 domain definition or mutational hotspot criteria established for BMPR1A
PP2 BMPR1A has pathogenic missense variants associated with disease (including non-truncating variants in familial colorectal cancer). However, no gene-specific missense constraint metric (e.g., Z-score, HCI prior probability) is available to determine whether the gene has a low rate of benign missense variation, which is a prerequisite for PP2 under generic ACMG/AMP rules. Details ▾Hide ▴
Evidence considered
- HCI prior not available for BMPR1A
- Literature supports pathogenic missense variants in BMPR1A
Still missing
- No gene-specific missense constraint metric (Z-score
- o/e
- HCI prior) available
Sources
41023686
PP4 No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for BMPR1A-associated disease (juvenile polyposis syndrome or hereditary colorectal cancer). Details ▾Hide ▴
Still missing
- No patient phenotype data available
BS2 No data are available on observation of NM_004329.3:c.398A>G in healthy adults in the absence of BMPR1A-associated disease. The variant is absent from gnomAD, which precludes evaluation of healthy carrier frequency. Details ▾Hide ▴
Still missing
- No healthy adult carrier data available
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on BMPR1A protein function were identified for this variant. Details ▾Hide ▴
Still missing
- No functional studies assessing p.Tyr133Cys for normal/benign effect
BS4 No segregation data are available for NM_004329.3:c.398A>G to evaluate whether the variant fails to segregate with disease in affected families. Details ▾Hide ▴
Still missing
- No family segregation data available
BP5 No data are available on an alternative molecular basis for disease in a patient harboring this variant. Without case-level information, BP5 cannot be assessed. Details ▾Hide ▴
Still missing
- No case-level data on alternative molecular diagnosis
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004329.3:c.398A>G is a missense variant (NP_004320.2:p.Tyr133Cys) and does not fall into the null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus variants) required for PVS1 application under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant classified as variant_bucket 'other' in PVS1 variant assessment
- apply_generic_pvs1_framework is false
Sources
BP2 N/ABMPR1A-related disorders (juvenile polyposis syndrome) follow autosomal dominant inheritance. Observation of this variant in trans with a pathogenic variant would require a homozygous state for a dominantly inherited condition, which is interpretively ambiguous and not standardly applied under BP2. Details ▾Hide ▴
Evidence considered
- BMPR1A-associated disease is autosomal dominant
BP7 N/ANM_004329.3:c.398A>G is a missense variant (p.Tyr133Cys) resulting in an amino acid substitution, not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. No applicable framework exists for this non-standard criterion. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- BMPR1A
- Transcript
- NM_004329.3
- Coding (HGVS c.)
- NM_004329.3:c.398A>G
- Protein (HGVS p.)
- NP_004320.2:p.(Tyr133Cys)
- GRCh38
- chr10:86899858 A>G
- GRCh37
- chr10:88659615 A>G
- ClinVar
- 824461
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…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in BMPR1A
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.623
- BayesDel
- 0.073
How the predictions were used
PP3 REVEL score of 0.623 is moderately elevated above the 0.5 threshold, suggesting possible deleterious effect. However, BayesDel score of 0.073 does not reach the deleterious threshold (typically >0.13), and SpliceAI max delta score is 0.00, predicting no splice impact. Multiple lines of computational evidence do not reach consensus for a deleterious effect, which is required for PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.623 (>0.5 threshold
- suggesting deleterious)
- BayesDel: 0.073 (<0.13 threshold
- not supporting deleterious)
- SpliceAI: max delta 0.00 (no splice impact predicted)
Sources
BP4 REVEL score of 0.623 is above the 0.5 threshold, suggesting possible deleterious effect rather than neutral impact. BayesDel score of 0.073 and SpliceAI max delta of 0.00 do not provide consensus support for a benign prediction. Multiple lines of computational evidence do not converge on a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.623 (above 0.5 threshold
- not supporting benign)
- BayesDel: 0.073 (neutral to slightly benign)
- SpliceAI: max delta 0.00 (neutral)
Sources
BP7 N/ANM_004329.3:c.398A>G is a missense variant (p.Tyr133Cys) resulting in an amino acid substitution, not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.623. BayesDel score = 0.0733129.
1 paper record 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
-
PMID 25394175 ↗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. · 2015No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/824461/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-88659615-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-86899858-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004329.3%3Ac.398A…
- OncoKB ↗www.oncokb.org/gene/BMPR1A/Y133C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BMPR1A+c.398A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 824461)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.623. BayesDel score = 0.0733129.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BMPR1A, a transmembrane receptor kinase, is frequently altered by mutation and deletion in various cancers, including colorectal and endometrial cance
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.