rs149403824

Variant names:

• chr12-55694828-T-G
• rs149403824
• NM_002206.3:c.2146A>C

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.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. 15/21 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 0.0031 (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:2 B:3
• Conservation: PhyloP100: -0.374
• Publications: 3 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: Benign. The variant received -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 VariationId is 383215.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.2146A>C	p.Met716Leu	missense	Exon 15 of 25	NP_002197.2	Q13683-7
	ITGA7	NM_001410977.1		c.2278A>C	p.Met760Leu	missense	Exon 16 of 26	NP_001397906.1	Q13683-1
	ITGA7	NM_001144996.2		c.2158A>C	p.Met720Leu	missense	Exon 15 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.2146A>C	p.Met716Leu	missense	Exon 15 of 25	ENSP00000257879.7	Q13683-7
	ITGA7	ENST00000553804.6	TSL:1	c.2158A>C	p.Met720Leu	missense	Exon 15 of 25	ENSP00000452120.1	Q13683-3
	ITGA7	ENST00000555728.5	TSL:5	c.2278A>C	p.Met760Leu	missense	Exon 16 of 26	ENSP00000452387.1	Q13683-1

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

GnomAD2 exomes AF: 0.000796 AC: 200 AN: 251330 AF XY: 0.000662

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 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

African (AFR) AF: 0.0108 AC: 360 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1112004

Other (OTH) AF: 0.00114 AC: 69 AN: 60396

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

African (AFR) AF: 0.0104 AC: 432 AN: 41342

American (AMR) AF: 0.00125 AC: 19 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67924

Other (OTH) AF: 0.00429 AC: 9 AN: 2100

Alfa AF: 0.00152 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.37
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.097
Sift	Benign	0.031	D
Sift4G	Benign	0.15	T
Polyphen		0.0	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs149403824; hg19: chr12-56088612;