chr10-86919210-A-C

Variant names:

• chr10-86919210-A-C
• rs1554891025
• NM_004329.3:c.907A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004329.3(BMPR1A):​c.907A>C​(p.Thr303Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T303I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

BMPR1A Gene-Disease associations (from GenCC):

• generalized juvenile polyposis/juvenile polyposis coli

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp
• juvenile polyposis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• polyposis syndrome, hereditary mixed, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hereditary mixed polyposis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• pulmonary arterial hypertension

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004329.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	NM_004329.3	MANE Select	c.907A>C	p.Thr303Pro	missense	Exon 10 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.982A>C	p.Thr328Pro	missense	Exon 11 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.955A>C	p.Thr319Pro	missense	Exon 11 of 14	NP_001393489.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	ENST00000372037.8	TSL:1 MANE Select	c.907A>C	p.Thr303Pro	missense	Exon 10 of 13	ENSP00000361107.2
	BMPR1A	ENST00000480152.3	TSL:3	c.907A>C	p.Thr303Pro	missense	Exon 11 of 14	ENSP00000483569.2
	BMPR1A	ENST00000713672.1		c.907A>C	p.Thr303Pro	missense	Exon 9 of 12	ENSP00000518974.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T303P variant (also known as c.907A>C), located in coding exon 8 of the BMPR1A gene, results from an A to C substitution at nucleotide position 907. The threonine at codon 303 is replaced by proline, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction by BayesDel for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.58		Loss of sheet (P = 0.302)
MVP		0.85
MPC		3.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.79
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1554891025; hg19: chr10-88678967;