Variant 2-181475034-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000885.6(ITGA4):c.394T>C(p.Ser132Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITGA4
NM_000885.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.17

Variant links:

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 links:

ITGA4 (HGNC:):

ITGA4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA4	NM_000885.6 linkuse as main transcript	c.394T>C	p.Ser132Pro	missense_variant	3/28	ENST00000397033.7	NP_000876.3	P13612-1
ITGA4	NM_001316312.2 linkuse as main transcript	c.394T>C	p.Ser132Pro	missense_variant	3/5		NP_001303241.1	P13612-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7 linkuse as main transcript	c.394T>C	p.Ser132Pro	missense_variant	3/28	1	NM_000885.6	ENSP00000380227.2		P13612-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.394T>C (p.S132P) alteration is located in exon 3 (coding exon 3) of the ITGA4 gene. This alteration results from a T to C substitution at nucleotide position 394, causing the serine (S) at amino acid position 132 to be replaced by a proline (P). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;D;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

D;T;D

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.1

M;M;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.8

D;N;D

REVEL

Uncertain

0.50

Sift

Benign

0.037

D;D;D

Sift4G

Benign

0.084

T;D;D

Polyphen

1.0, 0.98

.;D;D

Vest4

0.88

MutPred

0.52

Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);

MVP

0.86

MPC

1.4

ClinPred

0.99

GERP RS

4.1

Varity_R

0.82

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over