2-181475010-A-T

Variant names:

• chr2-181475010-A-T
• NM_000885.6:c.370A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000885.6(ITGA4):​c.370A>T​(p.Asn124Tyr) 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. 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: 3.14
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3537559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.370A>T	p.Asn124Tyr	missense_variant	Exon 3 of 28	ENST00000397033.7	NP_000876.3
ITGA4	NM_001316312.2	c.370A>T	p.Asn124Tyr	missense_variant	Exon 3 of 5		NP_001303241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7	c.370A>T	p.Asn124Tyr	missense_variant	Exon 3 of 28	1	NM_000885.6	ENSP00000380227.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.370A>T (p.N124Y) alteration is located in exon 3 (coding exon 3) of the ITGA4 gene. This alteration results from a A to T substitution at nucleotide position 370, causing the asparagine (N) at amino acid position 124 to be replaced by a tyrosine (Y). 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	0.18
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	.;D;.
Eigen	Benign	0.065
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	2.9	M;M;.
PhyloP100		3.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Benign	0.12
Sift	Benign	0.054	T;T;D
Sift4G	Benign	0.081	T;T;T
Polyphen		0.047, 0.12	.;B;B
Vest4		0.40
MutPred		0.60		Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);
MVP		0.81
MPC		0.91
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.43
gMVP		0.85
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

hg19: chr2-182339737;