rs201469044

Variant names:

• chr12-55698909-T-C
• rs201469044
• NM_002206.3:c.799A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001367994.1(ITGA7):​c.-494A>G variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: ITGA7 NM_001367994.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009333789).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000276 (42/152022) while in subpopulation AMR AF = 0.00164 (25/15284). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA7	NM_002206.3	c.799A>G	p.Ile267Val	missense_variant	Exon 6 of 25	ENST00000257879.11	NP_002197.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA7	ENST00000257879.11	c.799A>G	p.Ile267Val	missense_variant	Exon 6 of 25	1	NM_002206.3	ENSP00000257879.7

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

GnomAD2 exomes AF: 0.000204 AC: 49 AN: 240224 AF XY: 0.000161

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 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 AC: 49 AN: 33438

Gnomad4 AMR exome AF: 0.000271 AC: 12 AN: 44330

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26052

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39608

Gnomad4 SAS exome AF: 0.000443 AC: 38 AN: 85822

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53002

Gnomad4 NFE exome AF: 0.0000234 AC: 26 AN: 1110826

Gnomad4 Remaining exome AF: 0.000448 AC: 27 AN: 60272

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 AC: 0.000361864 AN: 0.000361864

Gnomad4 AMR AF: 0.00164 AC: 0.0016357 AN: 0.0016357

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.0002079 AN: 0.0002079

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000473 AC: 0.00047259 AN: 0.00047259

Alfa AF: 0.000110 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:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Sep 06, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 02, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Feb 15, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

May 20, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.0049	.;.;T;.;T;T
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
MutationAssessor	Benign	-1.6	.;.;.;.;N;.
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
Mutation Taster		=89/11	polymorphism

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;