Genetic Variant ITGA4:p.Thr356Ile (chr2-181485906-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000885.6(ITGA4):c.1067C>T(p.Thr356Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. T356R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ITGA4
NM_000885.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.884

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

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=0.07438484).

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.1067C>T	p.Thr356Ile	missense	Exon 10 of 28	NP_000876.3	P13612-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITGA4	ENST00000397033.7	TSL:1 MANE Select	c.1067C>T	p.Thr356Ile	missense	Exon 10 of 28	ENSP00000380227.2	P13612-1
ITGA4	ENST00000233573.6	TSL:1	c.1067C>T	p.Thr356Ile	missense	Exon 10 of 16	ENSP00000233573.6	E7EP60
ITGA4	ENST00000465522.5	TSL:2	n.1318C>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32900

American (AMR)

AF:

0.00

AC:

AN:

41640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25962

East Asian (EAS)

AF:

0.00

AC:

AN:

39046

South Asian (SAS)

AF:

0.00

AC:

AN:

83750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109748

Other (OTH)

AF:

0.00

AC:

AN:

60000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.7

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.21

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.52

M_CAP

Benign

0.0058

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.32

PhyloP100

0.88

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.43

REVEL

Benign

0.060

Sift

Benign

0.53

Sift4G

Benign

0.47

Polyphen

0.0090

Vest4

0.11

MutPred

0.34

Gain of sheet (P = 0.0827)

MVP

0.76

MPC

0.55

ClinPred

0.069

GERP RS

1.6

Varity_R

0.031

gMVP

0.67

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over