2-181509807-A-G

Variant names:

• chr2-181509807-A-G
• rs1143674
• NM_000885.6:c.1845A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000885.6(ITGA4):​c.1845A>G​(p.Thr615Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,595,064 control chromosomes in the GnomAD database, including 281,152 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.60 (28052 hom., cov: 31)
  • Exomes 𝑓: 0.59 (253100 hom.)
• Consequence: ITGA4 NM_000885.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001055
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 22 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP7: Synonymous conserved (PhyloP=1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.1845A>G	p.Thr615Thr	splice_region_variant, synonymous_variant	Exon 16 of 28	ENST00000397033.7	NP_000876.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7	c.1845A>G	p.Thr615Thr	splice_region_variant, synonymous_variant	Exon 16 of 28	1	NM_000885.6	ENSP00000380227.2
ITGA4	ENST00000476824.1	n.356A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 8	1
ITGA4	ENST00000490435.5	n.647A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5
ITGA4	ENST00000233573.6	c.*2A>G		downstream_gene_variant		1		ENSP00000233573.6

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91634 AN: 151822 Hom.: 28039 Cov.: 31

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.625

GnomAD2 exomes AF: 0.611 AC: 146491 AN: 239792 AF XY: 0.622

Gnomad AFR exome AF: 0.646

Gnomad AMR exome AF: 0.600

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.641

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.577

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.587 AC: 847105 AN: 1443124 Hom.: 253100 Cov.: 28 AF XY: 0.596 AC XY: 428055 AN XY: 718232

African (AFR) AF: 0.658 AC: 21440 AN: 32602

American (AMR) AF: 0.601 AC: 25711 AN: 42754

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 15719 AN: 25696

East Asian (EAS) AF: 0.622 AC: 24496 AN: 39360

South Asian (SAS) AF: 0.841 AC: 70216 AN: 83498

European-Finnish (FIN) AF: 0.460 AC: 24395 AN: 52986

Middle Eastern (MID) AF: 0.721 AC: 4114 AN: 5706

European-Non Finnish (NFE) AF: 0.568 AC: 625344 AN: 1100846

Other (OTH) AF: 0.598 AC: 35670 AN: 59676

GnomAD4 genome AF: 0.604 AC: 91700 AN: 151940 Hom.: 28052 Cov.: 31 AF XY: 0.604 AC XY: 44868 AN XY: 74264

African (AFR) AF: 0.654 AC: 27099 AN: 41466

American (AMR) AF: 0.616 AC: 9389 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2108 AN: 3472

East Asian (EAS) AF: 0.638 AC: 3286 AN: 5154

South Asian (SAS) AF: 0.836 AC: 4029 AN: 4820

European-Finnish (FIN) AF: 0.477 AC: 5039 AN: 10562

Middle Eastern (MID) AF: 0.675 AC: 197 AN: 292

European-Non Finnish (NFE) AF: 0.572 AC: 38872 AN: 67918

Other (OTH) AF: 0.620 AC: 1308 AN: 2108

Alfa AF: 0.589 Hom.: 47711

Bravo AF: 0.610

Asia WGS AF: 0.686 AC: 2380 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.6
DANN	Benign	0.85
PhyloP100		1.7
Mutation Taster		=13/187	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0
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: rs1143674; hg19: chr2-182374534; COSMIC: COSV52000521; COSMIC: COSV52000521;