chr10-86900115-C-G

Position:

• chr10-86900115-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_004329.3(BMPR1A):​c.519C>G​(p.Cys173Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.73

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 -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BMPR1A. . Gene score misZ 1.9176 (greater than the threshold 3.09). Trascript score misZ 3.8989 (greater than threshold 3.09). GenCC has associacion of gene with polyposis syndrome, hereditary mixed, 2, generalized juvenile polyposis/juvenile polyposis coli, hereditary mixed polyposis syndrome, pulmonary arterial hypertension, juvenile polyposis syndrome.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR1A	NM_004329.3	c.519C>G	p.Cys173Trp	missense_variant	7/13	ENST00000372037.8	NP_004320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR1A	ENST00000372037.8	c.519C>G	p.Cys173Trp	missense_variant	7/13	1	NM_004329.3	ENSP00000361107	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461290 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 15, 2023	This missense variant replaces cysteine with tryptophan at codon 173 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 not been reported in individuals affected with BMPR1A-related disorders in the literature. This variant has not been identified 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	Ambry Genetics	Mar 14, 2024	The p.C173W variant (also known as c.519C>G), located in coding exon 5 of the BMPR1A gene, results from a C to G substitution at nucleotide position 519. The cysteine at codon 173 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been detected in multiple individuals with no reported features of Juvenile polyposis syndrome (JPS) (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Juvenile polyposis syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 28, 2023	This missense variant replaces cysteine with tryptophan at codon 173 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 not been reported in individuals affected with BMPR1A-related disorders in the literature. This variant has not been identified 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	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the BMPR1A protein (p.Cys173Trp). This variant is not present in population databases (gnomAD no frequency). 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: 216583). 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. 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. -

Polyposis syndrome, hereditary mixed, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

BMPR1A-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

The BMPR1A c.519C>G variant is predicted to result in the amino acid substitution p.Cys173Trp. To our knowledge, this variant has not been reported in the literature or in gnomAD, indicating this variant is rare. This variant is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/216583/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.32	N
REVEL	Uncertain	0.45
Sift	Benign	0.070	T
Sift4G	Benign	0.13	T
Polyphen		0.23	B
Vest4		0.71
MutPred		0.55		Gain of MoRF binding (P = 0.0547);
MVP		0.98
MPC		0.75
ClinPred		0.38	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863224721; hg19: chr10-88659872;