rs146163713

chr12-55694089-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002206.3(ITGA7):c.2467G>A(p.Val823Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: ITGA7 NM_002206.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.542

Genes affected

ITGA7 (HGNC:6143): (integrin subunit alpha 7) The protein encoded by this gene belongs to the integrin alpha chain family. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. They mediate a wide spectrum of cell-cell and cell-matrix interactions, and thus play a role in cell migration, morphologic development, differentiation, and metastasis. This protein functions as a receptor for the basement membrane protein laminin-1. It is mainly expressed in skeletal and cardiac muscles and may be involved in differentiation and migration processes during myogenesis. Defects in this gene are associated with congenital myopathy. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15462959).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA7	NM_002206.3	c.2467G>A	p.Val823Met	missense_variant	19/25	ENST00000257879.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA7	ENST00000257879.11	c.2467G>A	p.Val823Met	missense_variant	19/25	1	NM_002206.3	A1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152260 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 32 AN: 251318 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000629 AC: 92 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000646 AC XY: 47 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular dystrophy due to integrin alpha-7 deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	This sequence change replaces valine with methionine at codon 823 of the ITGA7 protein (p.Val823Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs146163713, ExAC 0.04%). This variant has not been reported in the literature in individuals affected with ITGA7-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 25, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.051	N
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.96	N;N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.046	D;D;D;T;D
Sift4G	Uncertain	0.036	D;D;D;D;D
Polyphen		0.70	P;.;.;P;B
Vest4		0.33
MVP		0.37
MPC		0.48
ClinPred		0.11	T
GERP RS		2.5
Varity_R		0.052
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs146163713; hg19: chr12-56087873;