2-181480276-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000885.6(ITGA4):c.754+10A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,358,832 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (12 hom.)
• Consequence: ITGA4 NM_000885.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.23

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=-0.69).
• BP6: Variant 2-181480276-A-C is Benign according to our data. Variant chr2-181480276-A-C is described in ClinVar as [Benign]. Clinvar id is 785982.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1677/152186) while in subpopulation AFR AF= 0.0382 (1585/41542). AF 95% confidence interval is 0.0366. There are 23 homozygotes in gnomad4. There are 777 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1673 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA4	NM_000885.6	c.754+10A>C		intron_variant		ENST00000397033.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA4	ENST00000397033.7	c.754+10A>C		intron_variant		1	NM_000885.6	P1
ITGA4	ENST00000233573.6	c.754+10A>C		intron_variant		1
ITGA4	ENST00000465522.5	n.1005+10A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1673 AN: 152068 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00321 AC: 566 AN: 176084 Hom.: 5 AF XY: 0.00234 AC XY: 227 AN XY: 96900

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000261

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00109 AC: 1310 AN: 1206646 Hom.: 12 Cov.: 17 AF XY: 0.00105 AC XY: 633 AN XY: 602714

Gnomad4 AFR exome AF: 0.0362

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000336

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.0110 AC: 1677 AN: 152186 Hom.: 23 Cov.: 32 AF XY: 0.0104 AC XY: 777 AN XY: 74414

Gnomad4 AFR AF: 0.0382

Gnomad4 AMR AF: 0.00426

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00822 Hom.: 5

Bravo AF: 0.0127

Asia WGS AF: 0.00289 AC: 10 AN: 3470

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

Invitae

Apr 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs147352104; hg19: chr2-182345003;