rs11528010

Variant names:

• chr10-86876022-C-A
• rs11528010
• NM_004329.3:c.4C>A
• BMPR1A p.Pro2Thr

Your query was ambiguous. Multiple possible variants found:

• chr10-86876022-C-A
• chr10-86876022-C-T
• chr10-86876022-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004329.3(BMPR1A):​c.4C>A​(p.Pro2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,592,936 control chromosomes in the GnomAD database, including 83,045 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.40 (15021 hom., cov: 32)
  • Exomes 𝑓: 0.29 (68024 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18 O:2
• Conservation: PhyloP100: 3.20
• Publications: 54 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, G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.1856E-6).
• BP6: Variant 10-86876022-C-A is Benign according to our data. Variant chr10-86876022-C-A is described in ClinVar as Benign. ClinVar VariationId is 41782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	NM_004329.3	MANE Select	c.4C>A	p.Pro2Thr	missense	Exon 3 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.4C>A	p.Pro2Thr	missense	Exon 3 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.4C>A	p.Pro2Thr	missense	Exon 3 of 14	NP_001393489.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR1A	ENST00000372037.8	TSL:1 MANE Select	c.4C>A	p.Pro2Thr	missense	Exon 3 of 13	ENSP00000361107.2	P36894
	BMPR1A	ENST00000926286.1		c.4C>A	p.Pro2Thr	missense	Exon 3 of 14	ENSP00000596345.1
	BMPR1A	ENST00000480152.3	TSL:3	c.4C>A	p.Pro2Thr	missense	Exon 4 of 14	ENSP00000483569.2	P36894

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61375 AN: 151904 Hom.: 14968 Cov.: 32

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.389

GnomAD2 exomes AF: 0.358 AC: 89783 AN: 251114 AF XY: 0.343

Gnomad AFR exome AF: 0.668

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.718

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.286 AC: 411907 AN: 1440912 Hom.: 68024 Cov.: 31 AF XY: 0.285 AC XY: 204519 AN XY: 717892

African (AFR) AF: 0.679 AC: 22134 AN: 32594

American (AMR) AF: 0.385 AC: 17206 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 9840 AN: 25972

East Asian (EAS) AF: 0.717 AC: 28300 AN: 39448

South Asian (SAS) AF: 0.300 AC: 25686 AN: 85746

European-Finnish (FIN) AF: 0.362 AC: 19300 AN: 53312

Middle Eastern (MID) AF: 0.353 AC: 1888 AN: 5356

European-Non Finnish (NFE) AF: 0.245 AC: 268360 AN: 1094224

Other (OTH) AF: 0.322 AC: 19193 AN: 59612

GnomAD4 genome AF: 0.404 AC: 61474 AN: 152024 Hom.: 15021 Cov.: 32 AF XY: 0.408 AC XY: 30351 AN XY: 74304

African (AFR) AF: 0.660 AC: 27377 AN: 41472

American (AMR) AF: 0.349 AC: 5327 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1375 AN: 3468

East Asian (EAS) AF: 0.703 AC: 3634 AN: 5166

South Asian (SAS) AF: 0.315 AC: 1516 AN: 4818

European-Finnish (FIN) AF: 0.376 AC: 3966 AN: 10544

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.252 AC: 17128 AN: 67966

Other (OTH) AF: 0.390 AC: 825 AN: 2114

Alfa AF: 0.325 Hom.: 4121

Bravo AF: 0.421

EpiCase AF: 0.262

EpiControl AF: 0.260

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (6)
-	-	5	not specified (6)
-	-	4	Juvenile polyposis syndrome (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Generalized juvenile polyposis/juvenile polyposis coli (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.077
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0000032	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.81	N
PhyloP100		3.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.033
gMVP		0.37
Mutation Taster		=97/3	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11528010;

hg19: chr10-88635779;

COSMIC: COSV64409048;

Mutation Effect Viewer