rs567733221
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM1PP2PP3_ModerateBS1_SupportingBS2
The NM_004329.3(BMPR1A):c.1420G>C(p.Val474Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,614,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V474A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004329.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR1A | NM_004329.3 | c.1420G>C | p.Val474Leu | missense_variant | 12/13 | ENST00000372037.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR1A | ENST00000372037.8 | c.1420G>C | p.Val474Leu | missense_variant | 12/13 | 1 | NM_004329.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251494Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135922
GnomAD4 exome AF: 0.0000814 AC: 119AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58AN XY: 727248
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74488
ClinVar
Submissions by phenotype
Juvenile polyposis syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces valine with leucine at codon 474 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with history of Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 12/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 474 of the BMPR1A protein (p.Val474Leu). This variant is present in population databases (rs567733221, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 141060). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 15, 2023 | This missense variant replaces valine with leucine at codon 474 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with history of Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 12/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2022 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 17, 2019 | Variant summary: BMPR1A c.1420G>C (p.Val474Leu) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251494 control chromosomes. The observed variant frequency is higher than the estimated maximal expected allele frequency for a pathogenic variant in BMPR1A causing Juvenile Polyposis Syndrome phenotype (2e-06), suggesting that the variant is benign. c.1420G>C has been reported in the literature in an individual with history of Lynch syndrome-associated cancer and/or polyps (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. A co-occurrence with another pathogenic variant has been reported (CHEK2 c.1100delC, p.Thr367fsX15; in an internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Polyposis syndrome, hereditary mixed, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 27, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual undergoing multi-gene cancer panel testing due to a personal history of a Lynch syndrome-related cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 25980754) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at