Genetic Variant ITGA4:p.His961Gln (chr2-181534370-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_000885.6(ITGA4):c.2883T>G(p.His961Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000363 in 1,376,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H961H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ITGA4
NM_000885.6 missense, splice_region

Scores

Splicing: ADA: 0.0001095

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.518

Publications

27 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: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09049544).

BS2

High AC in GnomAdExome4 at 5 AD gene.

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.2883T>G	p.His961Gln	missense splice_region	Exon 26 of 28	NP_000876.3	P13612-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA4	ENST00000397033.7	TSL:1 MANE Select	c.2883T>G	p.His961Gln	missense splice_region	Exon 26 of 28	ENSP00000380227.2	P13612-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

246678

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

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

AF:

0.00000363

AC:

AN:

1376402

Hom.:

Cov.:

AF XY:

0.00000580

AC XY:

AN XY:

689838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31558

American (AMR)

AF:

0.00

AC:

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25572

East Asian (EAS)

AF:

0.00

AC:

AN:

39098

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

0.00000386

AC:

AN:

1035332

Other (OTH)

AF:

0.00

AC:

AN:

57370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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.:

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.46

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.15

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.59

M_CAP

Benign

0.026

MetaRNN

Benign

0.090

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.7

PhyloP100

-0.52

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.15

REVEL

Benign

0.047

Sift

Benign

0.34

Sift4G

Benign

0.18

Polyphen

0.031

Vest4

0.14

MutPred

0.44

Gain of sheet (P = 0.0477)

MVP

0.83

MPC

0.12

ClinPred

0.067

GERP RS

0.58

Varity_R

0.042

gMVP

0.43

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.058

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