2-181457703-C-G

Variant names:

• chr2-181457703-C-G
• rs762176587
• NM_000885.6:c.49C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000885.6(ITGA4):​c.49C>G​(p.Arg17Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 151,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R17W) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: ITGA4 NM_000885.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49
• 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]

ENSG00000307562 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12536961).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000885.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA4	NM_000885.6	MANE Select	c.49C>G	p.Arg17Gly	missense	Exon 1 of 28	NP_000876.3	P13612-1
	ITGA4	NM_001316312.2		c.49C>G	p.Arg17Gly	missense	Exon 1 of 5	NP_001303241.1	P13612-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA4	ENST00000397033.7	TSL:1 MANE Select	c.49C>G	p.Arg17Gly	missense	Exon 1 of 28	ENSP00000380227.2	P13612-1
	ITGA4	ENST00000233573.6	TSL:1	c.49C>G	p.Arg17Gly	missense	Exon 1 of 16	ENSP00000233573.6	E7EP60
	ITGA4	ENST00000339307.8	TSL:1	c.49C>G	p.Arg17Gly	missense	Exon 1 of 5	ENSP00000340149.4	P13612-2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151898 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242784 AF XY: 0.00000752

Gnomad AFR exome AF: 0.0000689

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151898 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74168

African (AFR) AF: 0.0000725 AC: 3 AN: 41354

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	2.1
DANN	Benign	0.81
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.5	L
PhyloP100		-1.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.41
Sift	Benign	0.23	T
Sift4G	Benign	0.55	T
Polyphen		0.057	B
Vest4		0.17
MutPred		0.47		Loss of MoRF binding (P = 0.0152)
MVP		0.74
MPC		0.67
ClinPred		0.025	T
GERP RS		0.087
PromoterAI		-0.024	Neutral
Varity_R		0.062
gMVP		0.55
Mutation Taster		=84/16	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: rs762176587; hg19: chr2-182322430;