rs149403824

Positions:

• chr12-55694828-T-G

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.2146A>C​(p.Met716Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000627 in 1,613,662 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (6 hom.)
• Consequence: ITGA7 NM_002206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.374

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=0.0103003085).
• BP6: Variant 12-55694828-T-G is Benign according to our data. Variant chr12-55694828-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 383215.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00306 (464/151778) while in subpopulation AFR AF= 0.0104 (432/41342). AF 95% confidence interval is 0.00964. There are 1 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA7	NM_002206.3	c.2146A>C	p.Met716Leu	missense_variant	15/25	ENST00000257879.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA7	ENST00000257879.11	c.2146A>C	p.Met716Leu	missense_variant	15/25	1	NM_002206.3	A1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 459 AN: 151660 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00433

GnomAD3 exomes AF: 0.000796 AC: 200 AN: 251330 Hom.: 0 AF XY: 0.000662 AC XY: 90 AN XY: 135862

Gnomad AFR exome AF: 0.00892

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000374 AC: 547 AN: 1461884 Hom.: 6 Cov.: 37 AF XY: 0.000366 AC XY: 266 AN XY: 727240

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00306 AC: 464 AN: 151778 Hom.: 1 Cov.: 32 AF XY: 0.00295 AC XY: 219 AN XY: 74170

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00429

Alfa AF: 0.000714 Hom.: 0

Bravo AF: 0.00326

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000898 AC: 109

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 10, 2016	- -

ITGA7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.92
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.82	T;T;T;T;T
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.62	N;N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.031	D;D;D;D;T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.0	B;.;.;B;B
Vest4		0.21
MutPred		0.53		.;.;.;.;Gain of sheet (P = 0.0827);
MVP		0.25
MPC		0.16
ClinPred		0.0033	T
GERP RS		3.4
Varity_R		0.13
gMVP		0.36

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

Other links and lift over

dbSNP: rs149403824; hg19: chr12-56088612;