2-181495455-T-C

Variant names:

• chr2-181495455-T-C
• rs2305586
• NM_000885.6:c.1385+39T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000885.6(ITGA4):​c.1385+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,478,834 control chromosomes in the GnomAD database, including 13,768 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1187 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12581 hom.)
• Consequence: ITGA4 NM_000885.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.551
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.1385+39T>C		intron_variant	Intron 13 of 27	ENST00000397033.7	NP_000876.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7	c.1385+39T>C		intron_variant	Intron 13 of 27	1	NM_000885.6	ENSP00000380227.2
ITGA4	ENST00000233573.6	c.1385+39T>C		intron_variant	Intron 13 of 15	1		ENSP00000233573.6
ITGA4	ENST00000473002.1	n.523+39T>C		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16289 AN: 152048 Hom.: 1183 Cov.: 32

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.155 AC: 38451 AN: 247900 AF XY: 0.155

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.259

Gnomad FIN exome AF: 0.0979

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.128 AC: 169898 AN: 1326670 Hom.: 12581 Cov.: 21 AF XY: 0.131 AC XY: 87182 AN XY: 667574

African (AFR) AF: 0.0224 AC: 686 AN: 30632

American (AMR) AF: 0.236 AC: 10431 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4833 AN: 25322

East Asian (EAS) AF: 0.273 AC: 10610 AN: 38926

South Asian (SAS) AF: 0.209 AC: 17430 AN: 83306

European-Finnish (FIN) AF: 0.0963 AC: 5128 AN: 53224

Middle Eastern (MID) AF: 0.123 AC: 679 AN: 5498

European-Non Finnish (NFE) AF: 0.114 AC: 112914 AN: 989594

Other (OTH) AF: 0.128 AC: 7187 AN: 55954

GnomAD4 genome AF: 0.107 AC: 16300 AN: 152164 Hom.: 1187 Cov.: 32 AF XY: 0.110 AC XY: 8165 AN XY: 74390

African (AFR) AF: 0.0262 AC: 1088 AN: 41524

American (AMR) AF: 0.161 AC: 2462 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 629 AN: 3466

East Asian (EAS) AF: 0.260 AC: 1343 AN: 5168

South Asian (SAS) AF: 0.215 AC: 1038 AN: 4818

European-Finnish (FIN) AF: 0.103 AC: 1096 AN: 10596

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8217 AN: 67984

Other (OTH) AF: 0.127 AC: 268 AN: 2116

Alfa AF: 0.121 Hom.: 2184

Bravo AF: 0.109

Asia WGS AF: 0.233 AC: 812 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.56
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2305586; hg19: chr2-182360182; COSMIC: COSV51997721; COSMIC: COSV51997721;