rs576247658

Positions:

• chr10-86921588-T-C
• chr10-86921588-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 5P and 9B. PM1 PP2 PP3_Moderate BP6 BS1 BS2

The NM_004329.3(BMPR1A):​c.1235T>C​(p.Val412Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,164 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V412G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4 O:1
• Conservation: PhyloP100: 7.96

Genes affected

BMPR1A (HGNC:1076): (bone morphogenetic protein receptor type 1A) The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases that include the type I receptors BMPR1A and BMPR1B and the type II receptor BMPR2. These receptors are also closely related to the activin receptors, ACVR1 and ACVR2. The ligands of these receptors are members of the TGF-beta superfamily. TGF-betas and activins transduce their signals through the formation of heteromeric complexes with 2 different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_004329.3
• PP2: Missense variant where missense usually causes diseases, BMPR1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844
• BP6: Variant 10-86921588-T-C is Benign according to our data. Variant chr10-86921588-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216576.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, not_provided=1, Likely_benign=3, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000131 (20/152292) while in subpopulation AFR AF= 0.000457 (19/41570). AF 95% confidence interval is 0.000299. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.1235T>C	p.Val412Ala	missense_variant	11/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.1235T>C	p.Val412Ala	missense_variant	11/13	1	NM_004329.3	P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251466 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135912

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727240

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74470

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Juvenile polyposis syndrome Uncertain:1 Benign:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 01-05-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
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 alanine at codon 412 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with breast cancer (PMID: 25186627) and an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 12/282860 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. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 07, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 26, 2023	This missense variant replaces valine with alanine at codon 412 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with breast cancer (PMID: 25186627) and an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 12/282860 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	Nov 03, 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 provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 09, 2017	Variant summary: The c.1235T>C (p.Val412Ala) in BPMR1A gene is a missense change that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the catalytic domain of the serine/threonine kinase, although the functional impact of this missense change is yet to be studied. The variant is present at a low frequency in large control population datasets of ExAC and gnomAD (0.000027; 3/121412 chrs tested and 0.00004; 12/277214 chrs tested, respectively) predominantly in individuals of African ancestry at frequencies that exceed the estimated maximal expected allele frequency of a pathogenic variant (0.000002). The variant has been reported in at least two affected individual (LS, BrC) via published reports and cited as VUS by a reputable database/diagnostic laboratory. In addition, the variant was identified in an unaffected individual undergoing genetic testing due to an extensive family history of BrC (three sisters and paternal aunt and 1st cousin). This individual also tested positive for a pathogenic mutation PMS2 c.2186_2187delTC p.L729fs*6 and likely pathogenic variant PALB2 c.801_802dupTA p.K268fs*12 (internal LCA data). Taken together, the variant was classified as Likely Benign until more data becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast cancer, Lynch syndrome-related cancer(s) and/or polyps or other cancers (PMID: 25186627, 25980754, 36315513, 32459922); This variant is associated with the following publications: (PMID: 25980754, 25186627, 36315513, 32459922) -

BMPR1A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2024

The BMPR1A c.1235T>C variant is predicted to result in the amino acid substitution p.Val412Ala. This variant has been reported in individuals with a history of breast cancer and suspected Lynch syndrome (Tung et al. 2015. PubMed ID: 25186627; Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/216576/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Generalized juvenile polyposis/juvenile polyposis coli Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 24, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.80
MPC		1.7
ClinPred		0.58	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.71
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs576247658; hg19: chr10-88681345;