2-181457778-C-G

Position:

• chr2-181457778-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000885.6(ITGA4):​c.124C>G​(p.Leu42Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGA4 NM_000885.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.512

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]

ITGA4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15731362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.124C>G	p.Leu42Val	missense_variant	1/28	ENST00000397033.7	NP_000876.3
ITGA4	NM_001316312.2	c.124C>G	p.Leu42Val	missense_variant	1/5		NP_001303241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7	c.124C>G	p.Leu42Val	missense_variant	1/28	1	NM_000885.6	ENSP00000380227.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.000240 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

The c.124C>G (p.L42V) alteration is located in exon 1 (coding exon 1) of the ITGA4 gene. This alteration results from a C to G substitution at nucleotide position 124, causing the leucine (L) at amino acid position 42 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.19	.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.28	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.41	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.82, 0.39	.;P;B
Vest4		0.25
MVP		0.83
MPC		0.53
ClinPred		0.20	T
GERP RS		3.6
Varity_R		0.18
gMVP		0.69

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: rs374066058; hg19: chr2-182322505;