Genetic Variant NM_000885.6:c.2633G>A (chr2-181530618-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000885.6(ITGA4):c.2633G>A(p.Arg878Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 1,611,264 control chromosomes in the GnomAD database, including 397,059 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.72 ( 39732 hom., cov: 32)

Exomes 𝑓: 0.70 ( 357327 hom. )

Consequence

ITGA4
NM_000885.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.93

Publications

48 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.6516366E-7).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6 link	c.2633G>A	p.Arg878Gln	missense_variant	Exon 24 of 28	ENST00000397033.7	NP_000876.3	P13612-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7 link	c.2633G>A	p.Arg878Gln	missense_variant	Exon 24 of 28	1	NM_000885.6	ENSP00000380227.2		P13612-1

Frequencies

GnomAD3 genomes

AF:

0.719

AC:

109299

AN:

151982

Hom.:

39708

Cov.:

show subpopulations

Gnomad AFR

AF:

0.751

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.777

Gnomad ASJ

AF:

0.672

Gnomad EAS

AF:

0.851

Gnomad SAS

AF:

0.888

Gnomad FIN

AF:

0.696

Gnomad MID

AF:

0.722

Gnomad NFE

AF:

0.675

Gnomad OTH

AF:

0.714

GnomAD2 exomes

AF:

0.738

AC:

183880

AN:

249130

AF XY:

0.741

show subpopulations

Gnomad AFR exome

AF:

0.753

Gnomad AMR exome

AF:

0.807

Gnomad ASJ exome

AF:

0.665

Gnomad EAS exome

AF:

0.847

Gnomad FIN exome

AF:

0.684

Gnomad NFE exome

AF:

0.676

Gnomad OTH exome

AF:

0.727

GnomAD4 exome

AF:

0.697

AC:

1017040

AN:

1459164

Hom.:

357327

Cov.:

AF XY:

0.703

AC XY:

510373

AN XY:

725984

show subpopulations

African (AFR)

AF:

0.753

AC:

25162

AN:

33416

American (AMR)

AF:

0.803

AC:

35876

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.671

AC:

17497

AN:

26080

East Asian (EAS)

AF:

0.840

AC:

33273

AN:

39626

South Asian (SAS)

AF:

0.885

AC:

76255

AN:

86166

European-Finnish (FIN)

AF:

0.688

AC:

36678

AN:

53330

Middle Eastern (MID)

AF:

0.762

AC:

4388

AN:

5760

European-Non Finnish (NFE)

AF:

0.672

AC:

745363

AN:

1109822

Other (OTH)

AF:

0.706

AC:

42548

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

14004

28008

42012

56016

70020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19392

38784

58176

77568

96960

<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

AF:

0.719

AC:

109377

AN:

152100

Hom.:

39732

Cov.:

AF XY:

0.726

AC XY:

53968

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.750

AC:

31131

AN:

41482

American (AMR)

AF:

0.777

AC:

11870

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.672

AC:

2334

AN:

3472

East Asian (EAS)

AF:

0.851

AC:

4410

AN:

5182

South Asian (SAS)

AF:

0.888

AC:

4283

AN:

4824

European-Finnish (FIN)

AF:

0.696

AC:

7356

AN:

10564

Middle Eastern (MID)

AF:

0.707

AC:

208

AN:

294

European-Non Finnish (NFE)

AF:

0.675

AC:

45895

AN:

67988

Other (OTH)

AF:

0.713

AC:

1501

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1563

3125

4688

6250

7813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

838

1676

2514

3352

4190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.694

Hom.:

97011

Bravo

AF:

0.721

TwinsUK

AF:

0.660

AC:

2448

ALSPAC

AF:

0.663

AC:

2554

ESP6500AA

AF:

0.752

AC:

2847

ESP6500EA

AF:

0.678

AC:

5596

ExAC

AF:

0.737

AC:

88991

Asia WGS

AF:

0.846

AC:

2941

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.032

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.11

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.13

MetaRNN

Benign

8.7e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

PhyloP100

-3.9

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.020

REVEL

Benign

0.023

Sift

Benign

0.38

Sift4G

Benign

0.47

Polyphen

0.063

Vest4

0.020

MPC

0.13

ClinPred

0.024

GERP RS

-11

Varity_R

0.014

gMVP

0.33

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over