rs1143676

Positions:

• chr2-181530618-G-A
• chr2-181530618-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000885.6(ITGA4):​c.2633G>A​(p.Arg878Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 1,611,264 control chromosomes in the GnomAD database, including 397,059 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.72 (39732 hom., cov: 32)
  • Exomes 𝑓: 0.70 (357327 hom.)
• Consequence: ITGA4 NM_000885.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.93

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.6516366E-7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA4	NM_000885.6	c.2633G>A	p.Arg878Gln	missense_variant	24/28	ENST00000397033.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA4	ENST00000397033.7	c.2633G>A	p.Arg878Gln	missense_variant	24/28	1	NM_000885.6	P1

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109299 AN: 151982 Hom.: 39708 Cov.: 32

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.777

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.851

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.696

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.714

GnomAD3 exomes AF: 0.738 AC: 183880 AN: 249130 Hom.: 68695 AF XY: 0.741 AC XY: 100122 AN XY: 135152

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.665

Gnomad EAS exome AF: 0.847

Gnomad SAS exome AF: 0.884

Gnomad FIN exome AF: 0.684

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.727

GnomAD4 exome AF: 0.697 AC: 1017040 AN: 1459164 Hom.: 357327 Cov.: 33 AF XY: 0.703 AC XY: 510373 AN XY: 725984

Gnomad4 AFR exome AF: 0.753

Gnomad4 AMR exome AF: 0.803

Gnomad4 ASJ exome AF: 0.671

Gnomad4 EAS exome AF: 0.840

Gnomad4 SAS exome AF: 0.885

Gnomad4 FIN exome AF: 0.688

Gnomad4 NFE exome AF: 0.672

Gnomad4 OTH exome AF: 0.706

GnomAD4 genome AF: 0.719 AC: 109377 AN: 152100 Hom.: 39732 Cov.: 32 AF XY: 0.726 AC XY: 53968 AN XY: 74350

Gnomad4 AFR AF: 0.750

Gnomad4 AMR AF: 0.777

Gnomad4 ASJ AF: 0.672

Gnomad4 EAS AF: 0.851

Gnomad4 SAS AF: 0.888

Gnomad4 FIN AF: 0.696

Gnomad4 NFE AF: 0.675

Gnomad4 OTH AF: 0.713

Alfa AF: 0.689 Hom.: 64346

Bravo AF: 0.721

TwinsUK AF: 0.660 AC: 2448

ALSPAC AF: 0.663 AC: 2554

ESP6500AA AF: 0.752 AC: 2847

ESP6500EA AF: 0.678 AC: 5596

ExAC AF: 0.737 AC: 88991

Asia WGS AF: 0.846 AC: 2941 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.032
DANN	Benign	0.84
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.023
Sift	Benign	0.38	T
Sift4G	Benign	0.47	T
Polyphen		0.063	B
Vest4		0.020
MPC		0.13
ClinPred		0.024	T
GERP RS		-11
Varity_R		0.014
gMVP		0.33

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: rs1143676; hg19: chr2-182395345; COSMIC: COSV67897468; COSMIC: COSV67897468;