rs149081471

Positions:

• chr12-55693284-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.2569G>A​(p.Gly857Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,082 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G857G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (8 hom.)
• Consequence: ITGA7 NM_002206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 7.48

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=0.026726931).
• BP6: Variant 12-55693284-C-T is Benign according to our data. Variant chr12-55693284-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94040.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr12-55693284-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00254 (386/152198) while in subpopulation NFE AF= 0.00488 (332/68020). AF 95% confidence interval is 0.00445. There are 0 homozygotes in gnomad4. There are 180 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA7	NM_002206.3	c.2569G>A	p.Gly857Ser	missense_variant	20/25	ENST00000257879.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA7	ENST00000257879.11	c.2569G>A	p.Gly857Ser	missense_variant	20/25	1	NM_002206.3	A1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00488

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00203 AC: 511 AN: 251472 Hom.: 1 AF XY: 0.00208 AC XY: 283 AN XY: 135916

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00400

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00368 AC: 5380 AN: 1461884 Hom.: 8 Cov.: 34 AF XY: 0.00355 AC XY: 2584 AN XY: 727244

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.00460

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00254 AC: 386 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74412

Gnomad4 AFR AF: 0.000892

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00488

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00401 Hom.: 2

Bravo AF: 0.00233

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00220 AC: 267

EpiCase AF: 0.00365

EpiControl AF: 0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

ITGA7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 16, 2020

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). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 29, 2024

Variant summary: ITGA7 c.2569G>A (p.Gly857Ser) results in a non-conservative amino acid change located in the Integrin alpha, third immunoglobulin-like domain (IPR048286) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 251472 control chromosomes, predominantly at a frequency of 0.004 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD (v4.0.0) strongly suggests that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2569G>A in individuals affected with Congenital Muscular Dystrophy Due To Integrin Alpha-7 Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 94040). Based on the evidence outlined above, the variant was classified as likely benign. -

Congenital muscular dystrophy due to integrin alpha-7 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.010	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0	D;.;.;P;P
Vest4		0.71
MVP		0.51
MPC		0.69
ClinPred		0.11	T
GERP RS		4.8
Varity_R		0.62
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs149081471; hg19: chr12-56087068;