rs200951235

Variant names:

• chr10-86900095-A-G
• rs200951235
• NM_004329.3:c.499A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-86900095-A-G
• chr10-86900095-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_004329.3(BMPR1A):​c.499A>G​(p.Met167Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. M167L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: BMPR1A NM_004329.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 2.67
• Publications: 6 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: Genomics England PanelApp, Orphanet, Ambry Genetics
• juvenile polyposis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30402088).
• BP6: Variant 10-86900095-A-G is Benign according to our data. Variant chr10-86900095-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188242.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000158 (231/1461694) while in subpopulation NFE AF = 0.0002 (222/1111996). AF 95% confidence interval is 0.000177. There are 0 homozygotes in GnomAdExome4. There are 112 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 10 AD,Unknown gene.

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.499A>G	p.Met167Val	missense	Exon 7 of 13	NP_004320.2
	BMPR1A	NM_001406559.1		c.499A>G	p.Met167Val	missense	Exon 7 of 14	NP_001393488.1
	BMPR1A	NM_001406560.1		c.499A>G	p.Met167Val	missense	Exon 7 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.499A>G	p.Met167Val	missense	Exon 7 of 13	ENSP00000361107.2	P36894
	BMPR1A	ENST00000926286.1		c.499A>G	p.Met167Val	missense	Exon 7 of 14	ENSP00000596345.1
	BMPR1A	ENST00000480152.3	TSL:3	c.499A>G	p.Met167Val	missense	Exon 8 of 14	ENSP00000483569.2	P36894

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251294 AF XY: 0.0000663

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000158 AC: 231 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.000154 AC XY: 112 AN XY: 727162

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1111996

Other (OTH) AF: 0.000132 AC: 8 AN: 60390

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74370

African (AFR) AF: 0.0000723 AC: 3 AN: 41466

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.25
Sift	Benign	0.49	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.61
MVP		0.84
MPC		0.40
ClinPred		0.048	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.51
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs200951235; hg19: chr10-88659852; COSMIC: COSV64409239;