rs537950420

chr12-55699989-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_002206.3(ITGA7):c.671G>C(p.Gly224Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000539 in 1,613,946 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: ITGA7 NM_002206.3 missense, splice_region
• Scores: Splicing: ADA: 0.9438
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.48

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40846604).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000342 (52/152096) while in subpopulation AMR AF= 0.00301 (46/15280). AF 95% confidence interval is 0.00232. There are 3 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA7	NM_002206.3	c.671G>C	p.Gly224Ala	missense_variant, splice_region_variant	5/25	ENST00000257879.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA7	ENST00000257879.11	c.671G>C	p.Gly224Ala	missense_variant, splice_region_variant	5/25	1	NM_002206.3	A1

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151978 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00295

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 251032 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135742

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152096 Hom.: 3 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74334

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.000786

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular dystrophy due to integrin alpha-7 deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 19, 2022	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 224 of the ITGA7 protein (p.Gly224Ala). This variant is present in population databases (rs537950420, gnomAD 0.01%). 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: 537988). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 09, 2023	PP3 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The c.671G>C (p.G224A) alteration is located in exon 5 (coding exon 5) of the ITGA7 gene. This alteration results from a G to C substitution at nucleotide position 671, causing the glycine (G) at amino acid position 224 to be replaced by an alanine (A). 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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;T;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	0.68	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PROVEAN	Pathogenic	-5.0	D;D;N;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Uncertain	0.026	D;D;T;.
Polyphen		1.0	.;.;D;.
Vest4		0.92
MutPred		0.65		.;.;Loss of sheet (P = 0.0315);.;
MVP		0.85
ClinPred		0.23	T
GERP RS		4.7
Varity_R		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.13		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: rs537950420; hg19: chr12-56093773;