20-57175004-T-C

Position:

• chr20-57175004-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001719.3(BMP7):​c.962A>G​(p.Asn321Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00363 in 1,610,820 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (43 hom.)
• Consequence: BMP7 NM_001719.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.76

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00505054).
• BP6: Variant 20-57175004-T-C is Benign according to our data. Variant chr20-57175004-T-C is described in ClinVar as [Benign]. Clinvar id is 771049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-57175004-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00343 (523/152332) while in subpopulation SAS AF= 0.0203 (98/4832). AF 95% confidence interval is 0.017. There are 1 homozygotes in gnomad4. There are 279 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 523 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP7	NM_001719.3	c.962A>G	p.Asn321Ser	missense_variant	5/7	ENST00000395863.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP7	ENST00000395863.8	c.962A>G	p.Asn321Ser	missense_variant	5/7	1	NM_001719.3	P1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 524 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00537 AC: 1332 AN: 248000 Hom.: 14 AF XY: 0.00622 AC XY: 835 AN XY: 134172

Gnomad AFR exome AF: 0.000682

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0190

Gnomad FIN exome AF: 0.000305

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00870

GnomAD4 exome AF: 0.00365 AC: 5330 AN: 1458488 Hom.: 43 Cov.: 32 AF XY: 0.00411 AC XY: 2982 AN XY: 725600

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0179

Gnomad4 FIN exome AF: 0.000237

Gnomad4 NFE exome AF: 0.00241

Gnomad4 OTH exome AF: 0.00507

GnomAD4 genome AF: 0.00343 AC: 523 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00375 AC XY: 279 AN XY: 74486

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00836

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00349 Hom.: 2

Bravo AF: 0.00349

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00537 AC: 652

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00517

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BMP7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 24, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital total pulmonary venous return anomaly Benign:1

Benign, no assertion criteria provided

case-control

Cytogenetics- Mohapatra Lab, Banaras Hindu University

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.31
DEOGEN2	Uncertain	0.46	T;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D;T;D
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.87	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.74	T;T;T
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.20
MVP		0.73
MPC		0.54
ClinPred		0.0060	T
GERP RS		4.0
Varity_R		0.083
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs61733438; hg19: chr20-55750060; COSMIC: COSV67779412; COSMIC: COSV67779412;