rs144983062

Variant names:

• chr12-55693209-C-T
• rs144983062
• NM_002206.3:c.2644G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002206.3(ITGA7):​c.2644G>A​(p.Glu882Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,078 control chromosomes in the GnomAD database, including 33 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (28 hom.)
• Consequence: ITGA7 NM_002206.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 2.60
• Publications: 14 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, Labcorp Genetics (formerly Invitae), Orphanet
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00966835).
• BP6: Variant 12-55693209-C-T is Benign according to our data. Variant chr12-55693209-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94041.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00343 (522/152226) while in subpopulation AMR AF = 0.00405 (62/15292). AF 95% confidence interval is 0.00361. There are 5 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

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.2644G>A	p.Glu882Lys	missense	Exon 20 of 25	NP_002197.2	Q13683-7
	ITGA7	NM_001410977.1		c.2776G>A	p.Glu926Lys	missense	Exon 21 of 26	NP_001397906.1	Q13683-1
	ITGA7	NM_001144996.2		c.2656G>A	p.Glu886Lys	missense	Exon 20 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.2644G>A	p.Glu882Lys	missense	Exon 20 of 25	ENSP00000257879.7	Q13683-7
	ITGA7	ENST00000553804.6	TSL:1	c.2656G>A	p.Glu886Lys	missense	Exon 20 of 25	ENSP00000452120.1	Q13683-3
	ITGA7	ENST00000555728.5	TSL:5	c.2776G>A	p.Glu926Lys	missense	Exon 21 of 26	ENSP00000452387.1	Q13683-1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 521 AN: 152108 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00426 AC: 1072 AN: 251460 AF XY: 0.00458

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00489

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00359 AC: 5243 AN: 1461852 Hom.: 28 Cov.: 33 AF XY: 0.00370 AC XY: 2691 AN XY: 727230

African (AFR) AF: 0.00108 AC: 36 AN: 33478

American (AMR) AF: 0.00257 AC: 115 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 736 AN: 26134

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

South Asian (SAS) AF: 0.00267 AC: 230 AN: 86254

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53420

Middle Eastern (MID) AF: 0.0199 AC: 115 AN: 5766

European-Non Finnish (NFE) AF: 0.00327 AC: 3634 AN: 1111982

Other (OTH) AF: 0.00556 AC: 336 AN: 60394

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152226 Hom.: 5 Cov.: 31 AF XY: 0.00323 AC XY: 240 AN XY: 74418

African (AFR) AF: 0.000771 AC: 32 AN: 41530

American (AMR) AF: 0.00405 AC: 62 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4818

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00400 AC: 272 AN: 68018

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00485 Hom.: 14

Bravo AF: 0.00383

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00400 AC: 486

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00599

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Congenital muscular dystrophy due to integrin alpha-7 deficiency (3)
-	-	3	not provided (3)
-	1	2	not specified (3)
-	-	1	ITGA7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Benign	0.012
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.099	T
Sift4G	Benign	0.54	T
Polyphen		0.31	B
Vest4		0.68
MVP		0.45
MPC		0.55
ClinPred		0.023	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144983062; hg19: chr12-56086993; COSMIC: COSV57691425; COSMIC: COSV57691425;