2-181482345-T-C

Variant names:

• chr2-181482345-T-C
• rs2305588
• NM_000885.6:c.841-15T>C

Variant summary

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

The NM_000885.6(ITGA4):​c.841-15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,586,036 control chromosomes in the GnomAD database, including 28,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2145 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26229 hom.)
• Consequence: ITGA4 NM_000885.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.504
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-181482345-T-C is Benign according to our data. Variant chr2-181482345-T-C is described in ClinVar as [Benign]. Clinvar id is 1270155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.841-15T>C		intron_variant	Intron 7 of 27	ENST00000397033.7	NP_000876.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7	c.841-15T>C		intron_variant	Intron 7 of 27	1	NM_000885.6	ENSP00000380227.2
ITGA4	ENST00000233573.6	c.841-15T>C		intron_variant	Intron 7 of 15	1		ENSP00000233573.6
ITGA4	ENST00000465522.5	n.1092-15T>C		intron_variant	Intron 7 of 9	2

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24351 AN: 152052 Hom.: 2143 Cov.: 32

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.172 AC: 38862 AN: 226520 AF XY: 0.175

Gnomad AFR exome AF: 0.0895

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.188 AC: 270003 AN: 1433866 Hom.: 26229 Cov.: 30 AF XY: 0.189 AC XY: 134399 AN XY: 712340

African (AFR) AF: 0.0867 AC: 2760 AN: 31830

American (AMR) AF: 0.133 AC: 5125 AN: 38418

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 6149 AN: 24880

East Asian (EAS) AF: 0.126 AC: 4958 AN: 39452

South Asian (SAS) AF: 0.165 AC: 13331 AN: 80852

European-Finnish (FIN) AF: 0.147 AC: 7763 AN: 52678

Middle Eastern (MID) AF: 0.242 AC: 1355 AN: 5590

European-Non Finnish (NFE) AF: 0.197 AC: 217358 AN: 1101030

Other (OTH) AF: 0.189 AC: 11204 AN: 59136

GnomAD4 genome AF: 0.160 AC: 24372 AN: 152170 Hom.: 2145 Cov.: 32 AF XY: 0.158 AC XY: 11753 AN XY: 74396

African (AFR) AF: 0.0889 AC: 3692 AN: 41522

American (AMR) AF: 0.150 AC: 2283 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 861 AN: 3468

East Asian (EAS) AF: 0.125 AC: 647 AN: 5184

South Asian (SAS) AF: 0.163 AC: 784 AN: 4816

European-Finnish (FIN) AF: 0.155 AC: 1639 AN: 10608

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.201 AC: 13697 AN: 68000

Other (OTH) AF: 0.177 AC: 374 AN: 2110

Alfa AF: 0.160 Hom.: 876

Bravo AF: 0.158

Asia WGS AF: 0.172 AC: 598 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 02, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.1
DANN	Benign	0.82
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

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: rs2305588; hg19: chr2-182347072; COSMIC: COSV52000680; COSMIC: COSV52000680;