NM_002206.3:c.1396G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_002206.3(ITGA7):c.1396G>A(p.Ala466Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A466A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ITGA7
NM_002206.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.56

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23990345).

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000274 (40/1461874) while in subpopulation AFR AF = 0.000806 (27/33480). AF 95% confidence interval is 0.000569. There are 0 homozygotes in GnomAdExome4. There are 21 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed 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 link	c.1396G>A	p.Ala466Thr	missense_variant	Exon 9 of 25	ENST00000257879.11	NP_002197.2	Q13683-7Q4LE35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA7	ENST00000257879.11 link	c.1396G>A	p.Ala466Thr	missense_variant	Exon 9 of 25	1	NM_002206.3	ENSP00000257879.7		Q13683-7

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251346

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000806

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112000

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000219

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

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

Jun 01, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 466 of the ITGA7 protein (p.Ala466Thr). This variant is present in population databases (rs61733964, gnomAD 0.03%). 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: 580306). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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 specified

Uncertain:1

Oct 24, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1396G>A (p.A466T) alteration is located in exon 9 (coding exon 9) of the ITGA7 gene. This alteration results from a G to A substitution at nucleotide position 1396, causing the alanine (A) at amino acid position 466 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

.;.;T;.;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.24

T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.7

.;.;.;.;L

PhyloP100

2.6

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.0

N;N;N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.013

D;D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D;D

Polyphen

0.45

B;.;.;P;P

Vest4

0.48

MVP

0.85

MPC

0.30

ClinPred

0.23

GERP RS

4.3

Varity_R

0.11

gMVP

0.48

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over