chr2-181480276-A-C

Variant names:

• chr2-181480276-A-C
• rs147352104
• NM_000885.6:c.754+10A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.23
• Publications: 0 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=-0.69).
• 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1677 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.754+10A>C		intron_variant	Intron 6 of 27	ENST00000397033.7	NP_000876.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7	c.754+10A>C		intron_variant	Intron 6 of 27	1	NM_000885.6	ENSP00000380227.2
ITGA4	ENST00000233573.6	c.754+10A>C		intron_variant	Intron 6 of 15	1		ENSP00000233573.6
ITGA4	ENST00000465522.5	n.1005+10A>C		intron_variant	Intron 6 of 9	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

GnomAD2 exomes AF: 0.00321 AC: 566 AN: 176084 AF XY: 0.00234

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 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

African (AFR) AF: 0.0362 AC: 919 AN: 25382

American (AMR) AF: 0.00255 AC: 67 AN: 26302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20298

East Asian (EAS) AF: 0.00 AC: 0 AN: 36002

South Asian (SAS) AF: 0.0000336 AC: 2 AN: 59494

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48346

Middle Eastern (MID) AF: 0.00580 AC: 20 AN: 3450

European-Non Finnish (NFE) AF: 0.000162 AC: 152 AN: 937192

Other (OTH) AF: 0.00297 AC: 149 AN: 50180

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

African (AFR) AF: 0.0382 AC: 1585 AN: 41542

American (AMR) AF: 0.00426 AC: 65 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67970

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00833 Hom.: 5

Bravo AF: 0.0127

Asia WGS AF: 0.00289 AC: 10 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

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: rs147352104; hg19: chr2-182345003;