12-55696405-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_002206.3(ITGA7):c.1765A>C(p.Ile589Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000787 in 1,601,496 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 2 hom. )

Consequence

ITGA7
NM_002206.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.31

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

congenital muscular dystrophy due to integrin alpha-7 deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
congenital fiber-type disproportion myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ITGA7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.39036027).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000315 (48/152198) while in subpopulation NFE AF = 0.000632 (43/68034). AF 95% confidence interval is 0.000482. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002206.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITGA7	NM_002206.3	MANE Select	c.1765A>C	p.Ile589Leu	missense	Exon 13 of 25	NP_002197.2
ITGA7	NM_001410977.1		c.1897A>C	p.Ile633Leu	missense	Exon 14 of 26	NP_001397906.1
ITGA7	NM_001144996.2		c.1777A>C	p.Ile593Leu	missense	Exon 13 of 25	NP_001138468.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITGA7	ENST00000257879.11	TSL:1 MANE Select	c.1765A>C	p.Ile589Leu	missense	Exon 13 of 25	ENSP00000257879.7
ITGA7	ENST00000553804.6	TSL:1	c.1777A>C	p.Ile593Leu	missense	Exon 13 of 25	ENSP00000452120.1
ITGA7	ENST00000555728.5	TSL:5	c.1897A>C	p.Ile633Leu	missense	Exon 14 of 26	ENSP00000452387.1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000359

AC:

AN:

231516

AF XY:

0.000313

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000347

Gnomad NFE exome

AF:

0.000662

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000837

AC:

1213

AN:

1449298

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

571

AN XY:

719604

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33368

American (AMR)

AF:

0.000230

AC:

AN:

43452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25738

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.00

AC:

AN:

83984

European-Finnish (FIN)

AF:

0.000285

AC:

AN:

52620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00106

AC:

1167

AN:

1104950

Other (OTH)

AF:

0.000301

AC:

AN:

59898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000315

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000521

Hom.:

Bravo

AF:

0.000366

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000289

AC:

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

Nov 01, 2022

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 leucine, which is neutral and non-polar, at codon 589 of the ITGA7 protein (p.Ile589Leu). This variant is present in population databases (rs200065922, gnomAD 0.06%). 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: 94034). 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. 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 22, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Apr 30, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.39

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.6

PhyloP100

5.3

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.33

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0070

Polyphen

0.88

Vest4

0.71

MVP

0.76

MPC

0.42

ClinPred

0.21

GERP RS

4.9

Varity_R

0.38

gMVP

0.51

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over