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BAP1c.37+28G>ALikely benign
Print report
Variant interpretation report

BAP1 c.37+28G>A, p.?

NM_004656.4:c.37+28G>A NP_004647.1:p.? 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 BAP1

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: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is present in gnomAD at very low frequency: 0.0107% in v2.1 (30/279376 alleles) and 0.0193% in v4.1 (312/1612888 alleles), both well below the 0.1% threshold for PM2 in non-VCEP contexts. The variant is absent from gnomAD-Canada. No homozygotes are observed in any database.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

SpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00). No donor gain, donor loss, acceptor gain, or acceptor loss is predicted. For an intronic variant where splicing is the primary functional concern, the absence of any predicted splice alteration supports a benign interpretation.

BP6Supporting
BP6 · supporting

Two reputable clinical testing laboratories have classified this variant as Likely benign in ClinVar: Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital (SCV007129130) and Labcorp Genetics, formerly Invitae (SCV004535795). Both submissions provide criteria for their classification (review status: criteria provided, single submitter). This meets BP6 criteria for a reputable source reporting the variant as 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: PM2 supporting, BP4 supporting, BP6 supporting; combination = 1 supporting + 2 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
312 / 1,612,888 alleles

gnomAD v4.1: 312 / 1,612,888 alleles. Recorded AF 0.000193442. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000107382; MAF= 0.01074%, 30/279376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000227644; MAF= 0.02276%, 29/127392 alleles, homozygotes = 0); grpmax FAF= 0.00016212.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00021772262138036142, 4/18372 alleles, homozygotes = 0).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

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

Applied · BP4 → SpliceAI ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

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

Context only COSMIC ↗
For specialists

Technical detail

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

26 criteria with recorded statuses: 3 met · 6 not met · 11 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

This variant is an intronic substitution (c.37+28G>A) in intron 1 of BAP1. SpliceAI predicts no splice impact (max delta = 0.00).

Two reputable clinical laboratories have independently classified this variant as Likely benign in ClinVar (Variation ID: 2906656).

The variant is present in gnomAD at low frequency: 0.0107% in v2.1 (30/279376 alleles) and 0.0193% in v4.1 (312/1612888 alleles), with no homozygotes in any database. This frequency is below the PM2 threshold of 0.1%.

Applying generic ACMG/AMP 2015 combination rules: one supporting pathogenic criterion (PM2) is outweighed by two supporting benign criteria (BP4, BP6), supporting a Likely benign classification.

Met · 3

PM2 SupportingThis variant is present in gnomAD at very low frequency: 0.0107% in v2.1 (30/279376 alleles) and 0.0193% in v4.1 (312/1612888 alleles), both well below the 0.1% threshold for PM2 in non-VCEP contexts. The variant is absent from gnomAD-Canada. No homozygotes are observed in any database. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 0.0107% (30/279376)
  • grpmax FAF = 0.000162
  • gnomAD v4.1 AF = 0.0193% (312/1612888)
  • grpmax FAF = 0.000222
  • Absent from gnomAD-Canada
  • No homozygotes in any population database
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingSpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00). No donor gain, donor loss, acceptor gain, or acceptor loss is predicted. For an intronic variant where splicing is the primary functional concern, the absence of any predicted splice alteration supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00
  • No predicted donor/acceptor gain or loss
  • No REVEL/BayesDel scores available (not missense)
Sources
spliceai ↗
BP6 SupportingTwo reputable clinical testing laboratories have classified this variant as Likely benign in ClinVar: Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital (SCV007129130) and Labcorp Genetics, formerly Invitae (SCV004535795). Both submissions provide criteria for their classification (review status: criteria provided, single submitter). This meets BP6 criteria for a reputable source reporting the variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 2906656: Likely benign
  • SCV007129130: Likely benign — Center for Genomic Medicine
  • Rigshospitalet
  • Copenhagen
  • SCV004535795: Likely benign — Labcorp Genetics (Invitae)
  • Both submissions are clinical testing with criteria provided
Sources
clinvar ↗

Not met · 6 · evaluated, threshold not reached

PM1 PM1 requires the variant to be located in a mutational hotspot or well-established critical functional domain. This variant is in intron 1 at position +28, not within any known functional domain, mutational hotspot, or critical residue. Hotspot analysis confirms the residue is not significant and the exact variant is not listed in any hotspot database. Details ▾Hide ▴
Evidence considered
  • Intronic position +28
  • outside any known functional domain
  • Hotspot analysis: residue not significant
  • exact variant not listed
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no splice impact (max delta = 0.00). REVEL and BayesDel scores are not available for this intronic variant. HCI prior is not supported for BAP1. No in silico evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 — no predicted splice impact
  • REVEL: not available (intronic
  • not missense)
  • BayesDel: not available
  • HCI prior: gene not supported
Sources
spliceai ↗
PP5 PP5 requires a reputable source to have recently reported the variant as pathogenic. ClinVar reports this variant as Likely benign from two clinical laboratories (SCV007129130, SCV004535795). No credible source reports this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign (2 clinical laboratories)
  • Variation ID: 2906656
  • No expert panel or other source reports this variant as pathogenic
Sources
clinvar ↗
BA1 BA1 requires an allele frequency >1% in population databases. This variant has an allele frequency of 0.0107% in gnomAD v2.1 and 0.0193% in gnomAD v4.1, both far below the 1% threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 0.0107%
  • gnomAD v4.1 AF = 0.0193%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 BS1 requires an allele frequency >0.3% in population databases (non-VCEP threshold). This variant has an allele frequency of 0.0107% in gnomAD v2.1 (grpmax FAF 0.016%) and 0.0193% in gnomAD v4.1 (grpmax FAF 0.022%), both well below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 0.0107%
  • grpmax FAF = 0.016%
  • gnomAD v4.1 AF = 0.0193%
  • grpmax FAF = 0.022%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. BAP1 tumor predisposition syndrome has incomplete penetrance (estimated 60-70%) and adult onset (median cancer diagnosis in the 40s-50s). The presence of this variant in gnomAD (30-312 heterozygotes) does not satisfy BS2 because reduced penetrance and late onset mean healthy adults in population databases may not have expressed the phenotype yet. Details ▾Hide ▴
Evidence considered
  • gnomAD: 30-312 heterozygotes observed across databases
  • BAP1 tumor predisposition syndrome: incomplete penetrance
  • adult onset
  • BS2 strict requirement of full penetrance at early age is not met
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 11 · no assessment recorded

PS2 PS2 requires a de novo variant with confirmed paternity and maternity. No de novo data are available for this variant in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PS3 PS3 requires well-established in vitro or in vivo functional studies supporting a damaging effect. No functional studies specific to NM_004656.4:c.37+28G>A were identified in the literature. The ClinVar-cited PMID 25741868 (ACMG guidelines) is a methodology paper that does not mention this variant. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies identified
PS4 PS4 requires the variant prevalence in affected individuals to be significantly increased compared to controls. While the variant is present in gnomAD at low frequency (v2.1: 30/279376, v4.1: 312/1612888), no case-control study or formal statistical comparison has been performed for this variant. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 30/279376 alleles (0.0107%)
  • gnomAD v4.1: 312/1612888 alleles (0.0193%)
  • No case-control comparison available
Still missing
  • No case-control data for affected vs. unaffected individuals
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM6 PM6 requires a de novo variant with confirmed paternity and maternity. No de novo data are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 PP1 requires co-segregation of the variant with disease in multiple affected family members. No segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No proband phenotype information is available for this case. Details ▾Hide ▴
Still missing
  • No proband phenotype data provided
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional studies specific to NM_004656.4:c.37+28G>A were identified. While SpliceAI predicts no splice impact (max delta = 0.00), this is in silico evidence covered under BP4, not BS3-level functional data. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 — in silico
  • not functional assay
Still missing
  • No variant-specific functional studies (e.g.
  • RNA analysis
  • minigene assay) identified
BS4 BS4 requires lack of segregation in affected members of a family. No segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 BP2 requires observation of the variant in trans with a pathogenic variant in a dominant disorder, or in cis with a pathogenic variant. No phasing data are available for this variant. Details ▾Hide ▴
Still missing
  • No phasing or co-occurrence data available
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available for this variant. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses in carriers
PS5 PS5 requires a de novo variant with confirmed paternity and maternity, where the variant is also reported as pathogenic by a reputable source. No de novo data are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is an intronic substitution (c.37+28G>A) located in intron 1 at position +28 from the exon 1 donor site. It does not fall into any ClinGen PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). SpliceAI predicts no splice impact (max delta = 0.00). PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Intronic variant at +28
  • not in canonical splice consensus
  • SpliceAI max delta = 0.00 — no predicted splice alteration
  • PVS1 variant assessment confirms variant bucket is 'other'
  • not eligible for generic PVS1
Sources
spliceai ↗pvs1_variant_assessmentpvs1_gene_context
PS1 N/APS1 requires a different pathogenic missense variant at the same amino acid position as the assessed variant. This variant is intronic (c.37+28G>A) and does not alter an amino acid. No protein consequence is predicted. Details ▾Hide ▴
Evidence considered
  • Intronic variant with no amino acid change
PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue. This variant is intronic (c.37+28G>A) and does not alter an amino acid. Protein consequence is indeterminate (NP_004647.1:p.?). PM5 candidate harvesting confirmed no eligible comparator variants. Details ▾Hide ▴
Evidence considered
  • Intronic variant with no protein residue — PM5 semantics cannot be applied
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common mechanism of disease. This variant is an intronic substitution (c.37+28G>A), not a missense variant. Details ▾Hide ▴
Evidence considered
  • Variant is intronic
  • not missense
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. BAP1 is indeed a gene where loss-of-function/truncating variants are the primary disease mechanism, but the assessed variant is intronic (c.37+28G>A), not a missense variant. BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant is intronic
  • not missense
  • BP1 is missense-specific
BP7 N/ABP7 applies to synonymous (silent) variants where splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. This variant is an intronic substitution (c.37+28G>A), not a synonymous exonic variant. BP7 is not applicable to intronic variants. Details ▾Hide ▴
Evidence considered
  • Variant is intronic
  • not synonymous/exonic

Identifiers

Gene
BAP1
Transcript
NM_004656.4
Coding (HGVS c.)
NM_004656.4:c.37+28G>A
Protein (HGVS p.)
NP_004647.1:p.?
GRCh38
chr3:52409814 C>T
GRCh37
chr3:52443830 C>T
ClinVar
2906656

Gene diagram

Every interpreted variant in BAP1, mapped onto the exon structure of NM_004656.4. Select a row to find it on the plot.

BAP1NM_004656.4
Fetching transcript structure from UCSC…
gnomAD v4.1 312 / 1,612,888 alleles AF 0.000193 · 0 homozygotes · FAF 0.000222
gnomAD v2.1 30 / 279,376 alleles AF 0.000107 · 0 homozygotes · FAF 0.000162
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00019 · 312 / 1,612,888 alleles · 0 hom · FAF 0.00022
Remaining individuals17 / 62,448 0.00027
European (non-Finnish)290 / 1,179,948 0.00025
Admixed American2 / 59,994 3.3e-05
African/African American2 / 74,934 2.7e-05
European (Finnish)1 / 63,106 1.6e-05
0 alternate alleles recorded in 5 other groups: Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 0.00011 · 30 / 279,376 alleles · 0 hom · FAF 0.00016
European (non-Finnish)29 / 127,392 0.00023
Remaining individuals1 / 7,132 0.00014
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000193442; MAF= 0.01934%, 312/1612888 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000272226; MAF= 0.02722%, 17/62448 alleles, homozygotes = 0); grpmax FAF= 0.00022226.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000107382; MAF= 0.01074%, 30/279376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000227644; MAF= 0.02276%, 29/127392 alleles, homozygotes = 0); grpmax FAF= 0.00016212.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00021772262138036142, 4/18372 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -95 bp
0.000
SpliceAI acceptor gainat -452 bp
0.000
SpliceAI donor lossat +193 bp
0.000
SpliceAI donor gainat +169 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingSpliceAI predicts no splicing impact for this intronic variant (max delta score = 0.00). No donor gain, donor loss, acceptor gain, or acceptor loss is predicted. For an intronic variant where splicing is the primary functional concern, the absence of any predicted splice alteration supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00
  • No predicted donor/acceptor gain or loss
  • No REVEL/BayesDel scores available (not missense)
Sources
spliceai ↗
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no splice impact (max delta = 0.00). REVEL and BayesDel scores are not available for this intronic variant. HCI prior is not supported for BAP1. No in silico evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 — no predicted splice impact
  • REVEL: not available (intronic
  • not missense)
  • BayesDel: not available
  • HCI prior: gene not supported
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants where splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. This variant is an intronic substitution (c.37+28G>A), not a synonymous exonic variant. BP7 is not applicable to intronic variants. Details ▾Hide ▴
Evidence considered
  • Variant is intronic
  • not synonymous/exonic

Statement

In silico

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

3 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
    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. This is the foundational ACMG/AMP 2015 classification framework paper. It does not mention NM_004656.4:c.37+28G>A or any BAP1-specific variant.
    Does not name this variant
    PMID 25741868 ↗
  • BAP1 Tumor Predisposition Syndrome.
    Adam MP et al. · 1993
    BAP1 Tumor Predisposition Syndrome — a GeneReviews clinical summary. This is a gene-level overview of BAP1-associated cancer predisposition. The publication provides general information about BAP1 germline variants and associated tumors (uveal melanoma, mesothelioma, renal cell carcinoma, cutaneous melanoma) but does not discuss the specific intronic variant NM_004656.4:c.37+28G>A.
    Does not name this variant
    PMID 27748099 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methodological paper describing the Sherloc variant classification framework. It does not mention NM_004656.4:c.37+28G>A or any BAP1-specific variant.
    Does not name this variant
    PMID 28492532 ↗

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

gnomAD v4.1 312 / 1,612,888 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 2 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗

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= 0.000193442; MAF= 0.01934%, 312/1612888 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000272226; MAF= 0.02722%, 17/62448 alleles, homozygotes = 0); grpmax FAF= 0.00022226.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000107382; MAF= 0.01074%, 30/279376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000227644; MAF= 0.02276%, 29/127392 alleles, homozygotes = 0); grpmax FAF= 0.00016212.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00021772262138036142, 4/18372 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories). (ClinVarID = 2906656)

In silico

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

Somatic

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