rs1554891022

chr10-86919190-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_004329.3(BMPR1A):c.887T>C(p.Ile296Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,668 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I296V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BMPR1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR1A	NM_004329.3	c.887T>C	p.Ile296Thr	missense_variant	10/13	ENST00000372037.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR1A	ENST00000372037.8	c.887T>C	p.Ile296Thr	missense_variant	10/13	1	NM_004329.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727144

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The p.I296T variant (also known as c.887T>C), located in coding exon 8 of the BMPR1A gene, results from a T to C substitution at nucleotide position 887. The isoleucine at codon 296 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Juvenile polyposis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BMPR1A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 296 of the BMPR1A protein (p.Ile296Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.38	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.49
Sift	Benign	0.065	T
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.79
MutPred		0.57		Gain of disorder (P = 0.0275);
MVP		0.85
MPC		3.1
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.35
gMVP		0.66

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: rs1554891022; hg19: chr10-88678947;