dbSNP rs55932635: BMPR1A:p.Val450Met (chr10-86923381-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP6BS1BS2

The NM_004329.3(BMPR1A):c.1348G>A(p.Val450Met) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V450L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

BMPR1A
NM_004329.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:6

Conservation

PhyloP100: 6.75

Publications

15 publications found

Variant links:

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

BMPR1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 26 uncertain in NM_004329.3

BP6

Variant 10-86923381-G-A is Benign according to our data. Variant chr10-86923381-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142024.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000789 (12/152096) while in subpopulation AMR AF = 0.00059 (9/15252). AF 95% confidence interval is 0.000307. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 12 Unknown,AD 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BMPR1A	NM_004329.3	MANE Select	c.1348G>A	p.Val450Met	missense	Exon 12 of 13	NP_004320.2
BMPR1A	NM_001406559.1		c.1423G>A	p.Val475Met	missense	Exon 13 of 14	NP_001393488.1
BMPR1A	NM_001406560.1		c.1396G>A	p.Val466Met	missense	Exon 13 of 14	NP_001393489.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BMPR1A	ENST00000372037.8	TSL:1 MANE Select	c.1348G>A	p.Val450Met	missense	Exon 12 of 13	ENSP00000361107.2	P36894
BMPR1A	ENST00000926286.1		c.1396G>A	p.Val466Met	missense	Exon 13 of 14	ENSP00000596345.1
BMPR1A	ENST00000480152.3	TSL:3	c.1348G>A	p.Val450Met	missense	Exon 13 of 14	ENSP00000483569.2	P36894

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000636

AC:

AN:

251480

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111994

Other (OTH)

AF:

0.0000662

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41402

American (AMR)

AF:

0.000590

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000737

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hereditary cancer-predisposing syndrome (3)

Juvenile polyposis syndrome (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.62

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.025

FATHMM_MKL

Pathogenic

0.97

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

1.6

PhyloP100

6.7

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.72

REVEL

Uncertain

0.40

Sift

Benign

0.099

Sift4G

Benign

0.19

Polyphen

0.24

Vest4

0.67

MVP

0.89

MPC

1.0

ClinPred

0.037

GERP RS

4.4

Varity_R

0.18

gMVP

0.74

Mutation Taster

=66/34

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over