chr12-55698884-C-T

Variant names:

• chr12-55698884-C-T
• rs74867235
• NM_002206.3:c.824G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367994.1(ITGA7):​c.-469G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 1,613,422 control chromosomes in the GnomAD database, including 2,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (128 hom., cov: 31)
  • Exomes 𝑓: 0.050 (2173 hom.)
• Consequence: ITGA7 NM_001367994.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0750
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020250678).
• BP6: Variant 12-55698884-C-T is Benign according to our data. Variant chr12-55698884-C-T is described in ClinVar as Benign. ClinVar VariationId is 94047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367994.1. 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.824G>A	p.Arg275His	missense	Exon 6 of 25	NP_002197.2	Q13683-7
	ITGA7	NM_001367994.1		c.-469G>A		5_prime_UTR_premature_start_codon_gain	Exon 5 of 24	NP_001354923.1
	ITGA7	NM_001410977.1		c.956G>A	p.Arg319His	missense	Exon 7 of 26	NP_001397906.1	Q13683-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA7	ENST00000257879.11	TSL:1 MANE Select	c.824G>A	p.Arg275His	missense	Exon 6 of 25	ENSP00000257879.7	Q13683-7
	ITGA7	ENST00000553804.6	TSL:1	c.836G>A	p.Arg279His	missense	Exon 6 of 25	ENSP00000452120.1	Q13683-3
	ITGA7	ENST00000555728.5	TSL:5	c.956G>A	p.Arg319His	missense	Exon 7 of 26	ENSP00000452387.1	Q13683-1

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5073 AN: 152090 Hom.: 128 Cov.: 31

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0551

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0328 AC: 8125 AN: 247600 AF XY: 0.0332

Gnomad AFR exome AF: 0.00897

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0453

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0199

Gnomad NFE exome AF: 0.0528

Gnomad OTH exome AF: 0.0315

GnomAD4 exome AF: 0.0504 AC: 73659 AN: 1461214 Hom.: 2173 Cov.: 33 AF XY: 0.0494 AC XY: 35892 AN XY: 726876

African (AFR) AF: 0.00911 AC: 305 AN: 33470

American (AMR) AF: 0.0144 AC: 645 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0463 AC: 1210 AN: 26124

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39696

South Asian (SAS) AF: 0.0212 AC: 1825 AN: 86178

European-Finnish (FIN) AF: 0.0220 AC: 1172 AN: 53226

Middle Eastern (MID) AF: 0.0227 AC: 131 AN: 5768

European-Non Finnish (NFE) AF: 0.0589 AC: 65487 AN: 1111742

Other (OTH) AF: 0.0477 AC: 2878 AN: 60368

GnomAD4 genome AF: 0.0333 AC: 5075 AN: 152208 Hom.: 128 Cov.: 31 AF XY: 0.0303 AC XY: 2255 AN XY: 74424

African (AFR) AF: 0.0101 AC: 419 AN: 41514

American (AMR) AF: 0.0232 AC: 354 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4826

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0551 AC: 3749 AN: 67980

Other (OTH) AF: 0.0402 AC: 85 AN: 2116

Alfa AF: 0.0422 Hom.: 332

Bravo AF: 0.0333

TwinsUK AF: 0.0623 AC: 231

ALSPAC AF: 0.0594 AC: 229

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.0528 AC: 454

ExAC AF: 0.0331 AC: 4019

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0522

EpiControl AF: 0.0494

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Congenital muscular dystrophy due to integrin alpha-7 deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.075
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.025
Sift	Benign	0.20	T
Sift4G	Benign	0.36	T
Polyphen		0.012	B
Vest4		0.17
MPC		0.22
ClinPred		0.018	T
GERP RS		2.6
Varity_R		0.050
gMVP		0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74867235; hg19: chr12-56092668; COSMIC: COSV57693762; COSMIC: COSV57693762;