2-181482345-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000885.6(ITGA4):c.841-15T>C variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.504

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

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
ITGA4	NM_000885.6	c.841-15T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000397033.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA4	ENST00000397033.7	c.841-15T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000885.6	P1
ITGA4	ENST00000233573.6	c.841-15T>C		splice_polypyrimidine_tract_variant, intron_variant		1
ITGA4	ENST00000465522.5	n.1092-15T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.172 AC: 38862 AN: 226520 Hom.: 3488 AF XY: 0.175 AC XY: 21546 AN XY: 122802

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 SAS exome AF: 0.163

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

Gnomad4 AFR exome AF: 0.0867

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.189

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

Gnomad4 AFR AF: 0.0889

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.177

Alfa AF: 0.147 Hom.: 480

Bravo AF: 0.158

Asia WGS AF: 0.172 AC: 598 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	9.1
Dann	Benign	0.82

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

Publications

LitVar

Other links and lift over

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