rs144983062

chr12-55693209-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002206.3(ITGA7):c.2644G>A(p.Glu882Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,078 control chromosomes in the GnomAD database, including 33 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 0.0034 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (28 hom.)
• Consequence: ITGA7 NM_002206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 2.60

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00966835).
• BP6: Variant 12-55693209-C-T is Benign according to our data. Variant chr12-55693209-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94041.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=2, Uncertain_significance=1}. Variant chr12-55693209-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-55693209-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00343 (522/152226) while in subpopulation AMR AF= 0.00405 (62/15292). AF 95% confidence interval is 0.00361. There are 5 homozygotes in gnomad4. There are 240 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA7	NM_002206.3	c.2644G>A	p.Glu882Lys	missense_variant	20/25	ENST00000257879.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA7	ENST00000257879.11	c.2644G>A	p.Glu882Lys	missense_variant	20/25	1	NM_002206.3	A1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 521 AN: 152108 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00426 AC: 1072 AN: 251460 Hom.: 8 AF XY: 0.00458 AC XY: 622 AN XY: 135916

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00489

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00359 AC: 5243 AN: 1461852 Hom.: 28 Cov.: 33 AF XY: 0.00370 AC XY: 2691 AN XY: 727230

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00267

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00327

Gnomad4 OTH exome AF: 0.00556

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152226 Hom.: 5 Cov.: 31 AF XY: 0.00323 AC XY: 240 AN XY: 74418

Gnomad4 AFR AF: 0.000771

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00400

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00542 Hom.: 10

Bravo AF: 0.00383

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00400 AC: 486

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00599

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant reported in homozygous state in individual with congenital fiber-type disproportion - individual had hypotonia but pulmonary phenotypes were not reported. However, variant has high frequency, 5 homozygotes are present in ExAC, and Emory classifies as benign. -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 19, 2020	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ITGA7: BP4, BS2 -

ITGA7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.012
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
MetaRNN	Benign	0.0097	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	0.89	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.099	T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T
Polyphen		0.31	B;.;.;B;B
Vest4		0.68
MVP		0.45
MPC		0.55
ClinPred		0.023	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144983062; hg19: chr12-56086993; COSMIC: COSV57691425; COSMIC: COSV57691425;