12-55685269-G-A

Position:

chr12-55685269-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_002206.3(ITGA7):c.3203C>T(p.Ala1068Val) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1068A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

ITGA7
NM_002206.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.78

Variant links:

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]

ITGA7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026728392).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000749 (114/152300) while in subpopulation NFE AF= 0.00137 (93/68022). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA7	NM_002206.3 linkuse as main transcript	c.3203C>T	p.Ala1068Val	missense_variant	25/25	ENST00000257879.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA7	ENST00000257879.11 linkuse as main transcript	c.3203C>T	p.Ala1068Val	missense_variant	25/25	1	NM_002206.3	A1	Q13683-7

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000796

AC:

200

AN:

251258

Hom.:

AF XY:

0.000854

AC XY:

116

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00111

AC:

1618

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

806

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000765

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.00128

Gnomad4 OTH exome

AF:

0.000960

GnomAD4 genome

AF:

0.000749

AC:

114

AN:

152300

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.000703

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000923

AC:

112

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital muscular dystrophy due to integrin alpha-7 deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1068 of the ITGA7 protein (p.Ala1068Val). This variant is present in population databases (rs139136931, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with developmental disorder (PMID: 31785789). This variant is also known as 12:56079053. ClinVar contains an entry for this variant (Variation ID: 470578). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2020

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

.;.;T;.;D

Eigen

Benign

-0.083

Eigen_PC

Benign

0.0066

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.49

T;T;T;T;T

MetaRNN

Benign

0.027

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;.;.;.;L

MutationTaster

Benign

0.91

D;D;D;D;D;D;D;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.0

N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.093

T;T;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.35

B;.;.;B;B

Vest4

0.24

MVP

0.30

MPC

0.17

ClinPred

0.014

GERP RS

4.2

Varity_R

0.050

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over