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.1 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.2 SpliceAI predicts no splicing impact (max delta score = 0.00), consistent with a benign synonymous variant.3 Thirteen clinical diagnostic laboratories have independently classified this variant as Benign or Likely benign in ClinVar (Variation ID 136525).4 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.5
BMPR1A
Final classification
Likely Benign
BMPR1A c.1299C>T · p.Phe433=
BMPR1A
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.
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.
Classification rationale
BS1BS2BP4BP6
Likely Benign
BMPR1A c.1299C>T
BS1 + BS2 + BP4 + BP6
→
Likely Benign
5
generic_acmg_combination_rules
Gene diagram
· NM_004329.3 · variants mapped to exon structure
BMPR1A
NM_004329.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 16 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
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.
gnomAD v2.1 African AF = 0.557% (139/24968 alleles1 homozygote)
✓
BS2
supporting
Benign
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.
gnomAD v2.1: 1 homozygote (Africanexome). gnomAD v4.1: 2 homozygotes (African). BMPR1A JPS is autosomal dominant with early-onset polyposis.
✓
BP4
supporting
Benign
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.
SpliceAI max delta = 0.00. No acceptor gainacceptor lossdonor gain
✓
BP6
supporting
Benign
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.
ClinVar Variation ID 136525: Benign by 8 clinical labsLikely benign by 4 clinical labsbenign by 1 clinical lab. Total 13 labs converging on benign/likely benign.
Assessed · not applied
Pathogenic
PS2
No de novo data available for this variant.
PS3
No functional data available for this synonymous variant.
PS4
No case-control enrichment data available.
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.
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%.
PM6
No de novo data available for this variant.
PP1
No segregation data available for this variant.
PP3
SpliceAI max delta = 0.00, and REVEL/BayesDel scores are not available.
PP4
No patient phenotype or clinical data available for independent assessment.
PP5
ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel).
Benign
BA1
gnomAD overall allele frequency is 0.06% (v2.1) and 0.034% (v4.1), both below the BA1 threshold of >1%.
BS3
No well-established functional studies demonstrating no deleterious effect are available for this variant.
BS4
No segregation data demonstrating lack of cosegregation with disease is available.
BP2
No data available regarding observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP5
No data available regarding an alternate molecular basis for disease in an individual carrying this variant.
BP7
This is a synonymous variant (p.Phe433=) with SpliceAI max delta = 0.00, satisfying two of three BP7 requirements.
N/A · 6
PVS1 · PS1 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006514657980456026, 12/18420 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.034%
· 545 / 1,614,170
2 hom · FAF 0.48%
2 hom · FAF 0.48%
African/African American 394 / 75,032 |
0.53% 2 hom |
Remaining individuals 54 / 62,510 |
0.086% |
Admixed American 46 / 60,020 |
0.077% |
Middle Eastern 3 / 6,062 |
0.049% |
East Asian 3 / 44,886 |
0.0067% |
South Asian 4 / 91,080 |
0.0044% |
European (non-Finnish) 41 / 1,180,028 |
0.0035% |
+ 3 not observed (European (Finnish), Amish, Ashkenazi Jewish)
gnomAD v2.1
0.06%
· 171 / 282,898
1 hom · FAF 0.48%
1 hom · FAF 0.48%
African/African American 139 / 24,968 |
0.56% 1 hom |
Admixed American 25 / 35,440 |
0.071% |
East Asian 1 / 19,954 |
0.005% |
European (non-Finnish) 5 / 129,200 |
0.0039% |
South Asian 1 / 30,616 |
0.0033% |
+ 3 not observed (Ashkenazi Jewish, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
0.065%
· 12 / 18,420
0 hom · FAF 0.39%
0 hom · FAF 0.39%
indel · split
African/African American 8 / 1,020 |
0.78% |
East Asian 2 / 1,338 |
0.15% |
Latino/Admixed American 1 / 838 |
0.12% |
Remaining individuals 1 / 1,138 |
0.088% |
+ 5 not observed (Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish), South Asian)
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
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
25741868 ↗
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.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
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.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
35802134 ↗
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).
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR