rs201469044

chr12-55698909-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002206.3(ITGA7):c.799A>G(p.Ile267Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,611,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. I267T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: ITGA7 NM_002206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.419

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009333789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA7	NM_002206.3	c.799A>G	p.Ile267Val	missense_variant	6/25	ENST00000257879.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA7	ENST00000257879.11	c.799A>G	p.Ile267Val	missense_variant	6/25	1	NM_002206.3	A1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 151904 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000204 AC: 49 AN: 240224 Hom.: 0 AF XY: 0.000161 AC XY: 21 AN XY: 130832

Gnomad AFR exome AF: 0.000469

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000768

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000466

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1459114 Hom.: 1 Cov.: 33 AF XY: 0.000114 AC XY: 83 AN XY: 725634

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.000271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000443

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152022 Hom.: 0 Cov.: 31 AF XY: 0.000417 AC XY: 31 AN XY: 74306

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000971 Hom.: 0

Bravo AF: 0.000431

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital muscular dystrophy due to integrin alpha-7 deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 06, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 267 of the ITGA7 protein (p.Ile267Val). This variant is present in population databases (rs201469044, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with ITGA7-related conditions. ClinVar contains an entry for this variant (Variation ID: 538001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITGA7 protein function with a negative predictive value of 80%. 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	9.9
Dann	Benign	0.94
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.76	T;T;T;T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0093	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.96	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.21	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;.
Polyphen		0.0060	B;.;.;B;B;.
Vest4		0.20
MVP		0.26
MPC		0.14
ClinPred		0.014	T
GERP RS		4.5
Varity_R		0.052
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201469044; hg19: chr12-56092693;