Variant classification summary

NM_004329.3:c.1299C>T

BMPR1A · NP_004320.2:p.(Phe433=) · NM_004329.3

GRCh37: chr10:88681409 C>T · GRCh38: chr10:86921652 C>T

Gene: BMPR1A Transcript: NM_004329.3

Final call

Likely Benign

BS1 strong benign BS2 supporting benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

BMPR1A

Transcript

NM_004329.3

Protein

NP_004320.2:p.(Phe433=)

gnomAD AF

0.00033763482161110664 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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

4

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

5

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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).	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 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.
PS2	Not met	No de novo data available for this variant.
PS3	Not met	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.	spliceai
PS4	Not met	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.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 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.
PM1	Not met	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.	spliceai
PM2	Not met	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.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not met	No de novo data available for this variant.
PP1	Not met	No segregation data available for this variant.
PP2	N/A	PP2 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.
PP3	Not met	SpliceAI max delta = 0.00, and REVEL/BayesDel scores are not available. No in silico evidence of a deleterious effect is present.	spliceai
PP4	Not met	No patient phenotype or clinical data available for independent assessment.
PP5	Not met	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.	clinvar
BA1	Not met	gnomAD overall allele frequency is 0.06% (v2.1) and 0.034% (v4.1), both below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Met	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 gnomad_v4
BS2	Met	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 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease is available.
BP1	N/A	BP1 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.
BP2	Not met	No data available regarding observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions; this is a single nucleotide substitution.
BP4	Met	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
BP5	Not met	No data available regarding an alternate molecular basis for disease in an individual carrying this variant.
BP6	Met	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
BP7	Not assessed	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.	spliceai

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