2-181534370-T-C

Variant names:

• chr2-181534370-T-C
• rs7562325
• NM_000885.6:c.2883T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000885.6(ITGA4):​c.2883T>C​(p.His961His) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,522,244 control chromosomes in the GnomAD database, including 268,253 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.60 (27810 hom., cov: 31)
  • Exomes 𝑓: 0.59 (240443 hom.)
• Consequence: ITGA4 NM_000885.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0007010
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.518
• Publications: 27 publications found

Genes affected

ITGA4 (HGNC:6140): (integrin subunit alpha 4) The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 4 subunit. This subunit associates with a beta 1 or beta 7 subunit to form an integrin that may play a role in cell motility and migration. This integrin is a therapeutic target for the treatment of multiple sclerosis, Crohn's disease and inflammatory bowel disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP7: Synonymous conserved (PhyloP=-0.518 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000885.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA4	NM_000885.6	MANE Select	c.2883T>C	p.His961His	splice_region synonymous	Exon 26 of 28	NP_000876.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA4	ENST00000397033.7	TSL:1 MANE Select	c.2883T>C	p.His961His	splice_region synonymous	Exon 26 of 28	ENSP00000380227.2

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91404 AN: 151852 Hom.: 27797 Cov.: 31

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.624

GnomAD2 exomes AF: 0.614 AC: 151532 AN: 246678 AF XY: 0.625

Gnomad AFR exome AF: 0.630

Gnomad AMR exome AF: 0.604

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.636

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.587 AC: 804468 AN: 1370274 Hom.: 240443 Cov.: 22 AF XY: 0.597 AC XY: 410117 AN XY: 687016

African (AFR) AF: 0.635 AC: 19968 AN: 31430

American (AMR) AF: 0.606 AC: 26960 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 15581 AN: 25534

East Asian (EAS) AF: 0.618 AC: 24130 AN: 39064

South Asian (SAS) AF: 0.837 AC: 70314 AN: 83990

European-Finnish (FIN) AF: 0.490 AC: 26098 AN: 53258

Middle Eastern (MID) AF: 0.721 AC: 4022 AN: 5582

European-Non Finnish (NFE) AF: 0.566 AC: 583299 AN: 1029746

Other (OTH) AF: 0.596 AC: 34096 AN: 57164

GnomAD4 genome AF: 0.602 AC: 91470 AN: 151970 Hom.: 27810 Cov.: 31 AF XY: 0.604 AC XY: 44855 AN XY: 74282

African (AFR) AF: 0.635 AC: 26328 AN: 41464

American (AMR) AF: 0.617 AC: 9400 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 2115 AN: 3472

East Asian (EAS) AF: 0.633 AC: 3277 AN: 5174

South Asian (SAS) AF: 0.831 AC: 4005 AN: 4820

European-Finnish (FIN) AF: 0.507 AC: 5345 AN: 10550

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39147 AN: 67932

Other (OTH) AF: 0.620 AC: 1309 AN: 2110

Alfa AF: 0.591 Hom.: 76686

Bravo AF: 0.606

Asia WGS AF: 0.680 AC: 2363 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.42
DANN	Benign	0.77
PhyloP100		-0.52
Mutation Taster		=45/55	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00070
dbscSNV1_RF	Benign	0.058
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: rs7562325; hg19: chr2-182399097; COSMIC: COSV59207843; COSMIC: COSV59207843;