rs1060499775

Variant names:

• chr12-55707550-C-CT
• rs1060499775
• NM_002206.3:c.132_133insA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002206.3(ITGA7):​c.132_133insA​(p.Glu45ArgfsTer58) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K44K) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ITGA7 NM_002206.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.58
• 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-55707550-C-CT is Pathogenic according to our data. Variant chr12-55707550-C-CT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402212.Status of the report is criteria_provided_single_submitter, 1 stars.

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.132_133insA	p.Glu45ArgfsTer58	frameshift	Exon 1 of 25	NP_002197.2	Q13683-7
	ITGA7	NM_001410977.1		c.132_133insA	p.Glu45ArgfsTer58	frameshift	Exon 1 of 26	NP_001397906.1	Q13683-1
	ITGA7	NM_001144996.2		c.132_133insA	p.Glu45ArgfsTer58	frameshift	Exon 1 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.132_133insA	p.Glu45ArgfsTer58	frameshift	Exon 1 of 25	ENSP00000257879.7	Q13683-7
	ITGA7	ENST00000553804.6	TSL:1	c.132_133insA	p.Glu45ArgfsTer58	frameshift	Exon 1 of 25	ENSP00000452120.1	Q13683-3
	ITGA7	ENST00000555728.5	TSL:5	c.132_133insA	p.Glu45ArgfsTer58	frameshift	Exon 1 of 26	ENSP00000452387.1	Q13683-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal brain morphology (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=0/200	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1060499775;

hg19: chr12-56101334;