Genetic Variant BMP7:p.Ile386Leu (chr20-57171099-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001719.3(BMP7):c.1156A>C(p.Ile386Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I386V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BMP7
NM_001719.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

0 publications found

Variant links:

Genes affected

BMP7 (HGNC:1074): (bone morphogenetic protein 7) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer, which plays a role in bone, kidney and brown adipose tissue development. Additionally, this protein induces ectopic bone formation and may promote fracture healing in human patients. [provided by RefSeq, Jul 2016]

BMP7 Gene-Disease associations (from GenCC):

multiple congenital anomalies/dysmorphic syndrome
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
hypospadias
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BMP7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29943568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP7	NM_001719.3 link	c.1156A>C	p.Ile386Leu	missense_variant	Exon 7 of 7	ENST00000395863.8	NP_001710.1	P18075A8K571

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BMP7	ENST00000395863.8 link	c.1156A>C	p.Ile386Leu	missense_variant	Exon 7 of 7	1	NM_001719.3	ENSP00000379204.3	P18075
BMP7	ENST00000395864.7 link	c.958A>C	p.Ile320Leu	missense_variant	Exon 6 of 6	5		ENSP00000379205.3	B1AKZ9
BMP7	ENST00000460817.5 link	n.656A>C		non_coding_transcript_exon_variant	Exon 6 of 6	3
BMP7	ENST00000476877.1 link	n.400A>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

D;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.099

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

-1.1

N;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.23

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.10

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.0010

B;B

Vest4

0.48

MutPred

0.56

Gain of catalytic residue at I386 (P = 0.0516);.;

MVP

0.91

MPC

0.95

ClinPred

0.94

GERP RS

5.2

Varity_R

0.50

gMVP

0.78

Mutation Taster

=24/76

disease causing

(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

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chr20-57171099-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over