rs201594532

Variant names:

• chr12-55698816-G-A
• rs201594532
• NM_002206.3:c.892C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_002206.3(ITGA7):​c.892C>T​(p.Arg298Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: ITGA7 NM_002206.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.648
• Publications: 1 publications found

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, Orphanet, Labcorp Genetics (formerly Invitae)
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36246237).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000197 (30/152222) while in subpopulation AFR AF = 0.000674 (28/41548). AF 95% confidence interval is 0.000478. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002206.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA7	NM_002206.3	MANE Select	c.892C>T	p.Arg298Cys	missense	Exon 6 of 25	NP_002197.2	Q13683-7
	ITGA7	NM_001410977.1		c.1024C>T	p.Arg342Cys	missense	Exon 7 of 26	NP_001397906.1	Q13683-1
	ITGA7	NM_001144996.2		c.904C>T	p.Arg302Cys	missense	Exon 6 of 25	NP_001138468.1	Q13683-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA7	ENST00000257879.11	TSL:1 MANE Select	c.892C>T	p.Arg298Cys	missense	Exon 6 of 25	ENSP00000257879.7	Q13683-7
	ITGA7	ENST00000553804.6	TSL:1	c.904C>T	p.Arg302Cys	missense	Exon 6 of 25	ENSP00000452120.1	Q13683-3
	ITGA7	ENST00000555728.5	TSL:5	c.1024C>T	p.Arg342Cys	missense	Exon 7 of 26	ENSP00000452387.1	Q13683-1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000997 AC: 25 AN: 250718 AF XY: 0.000110

Gnomad AFR exome AF: 0.000619

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461798 Hom.: 0 Cov.: 33 AF XY: 0.0000770 AC XY: 56 AN XY: 727212

African (AFR) AF: 0.00128 AC: 43 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112002

Other (OTH) AF: 0.0000993 AC: 6 AN: 60394

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74424

African (AFR) AF: 0.000674 AC: 28 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Congenital muscular dystrophy due to integrin alpha-7 deficiency (2)
-	2	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.33	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.0098	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.65
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.65
MVP		0.85
MPC		0.80
ClinPred		0.32	T
GERP RS		3.5
Varity_R		0.41
gMVP		0.63
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs201594532; hg19: chr12-56092600; COSMIC: COSV57702630; COSMIC: COSV57702630;