rs749679578

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000257879.11(ITGA7):​c.1982C>T​(p.Thr661Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,605,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. T661T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ITGA7
ENST00000257879.11 missense

Scores

3
16

Clinical Significance

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

Conservation

PhyloP100: 0.867
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13428485).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ITGA7NM_002206.3 linkuse as main transcriptc.1982C>T p.Thr661Met missense_variant 14/25 ENST00000257879.11 NP_002197.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ITGA7ENST00000257879.11 linkuse as main transcriptc.1982C>T p.Thr661Met missense_variant 14/251 NM_002206.3 ENSP00000257879 A1Q13683-7

Frequencies

GnomAD3 genomes
AF:
0.0000199
AC:
3
AN:
150420
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000132
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251444
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1455050
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
723840
show subpopulations
Gnomad4 AFR exome
AF:
0.0000601
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000994
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000199
AC:
3
AN:
150420
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
73306
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000132
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 661 of the ITGA7 protein (p.Thr661Met). This variant is present in population databases (rs749679578, gnomAD 0.007%). 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: 470571). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 12, 2022- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 07, 2020Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this 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
0.080
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.015
.;.;T;.;T
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.16
FATHMM_MKL
Benign
0.61
D
LIST_S2
Benign
0.77
T;T;T;T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.13
T;T;T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Uncertain
2.3
.;.;.;.;M
MutationTaster
Benign
0.98
D;D;D;D;D;D;D;D
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.9
N;N;N;N;N
REVEL
Benign
0.16
Sift
Benign
0.081
T;T;T;T;T
Sift4G
Benign
0.095
T;T;T;T;T
Polyphen
0.84
P;.;.;P;D
Vest4
0.29
MutPred
0.45
.;.;.;.;Gain of catalytic residue at T705 (P = 0.1027);
MVP
0.54
MPC
0.19
ClinPred
0.16
T
GERP RS
4.8
Varity_R
0.060
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs749679578; hg19: chr12-56089327; API