Genetic Variant NM_002208.5:c.2676G>C (chr17-3732446-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_002208.5(ITGAE):c.2676G>C(p.Gln892His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 1,613,628 control chromosomes in the GnomAD database, including 4,012 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.080 ( 674 hom., cov: 32)

Exomes 𝑓: 0.058 ( 3338 hom. )

Consequence

ITGAE
NM_002208.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.798

Publications

19 publications found

Variant links:

Genes affected

ITGAE (HGNC:6147): (integrin subunit alpha E) Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This gene encodes an I-domain-containing alpha integrin that undergoes post-translational cleavage in the extracellular domain, yielding disulfide-linked heavy and light chains. In combination with the beta 7 integrin, this protein forms the E-cadherin binding integrin known as the human mucosal lymphocyte-1 antigen. This protein is preferentially expressed in human intestinal intraepithelial lymphocytes (IEL), and in addition to a role in adhesion, it may serve as an accessory molecule for IEL activation. [provided by RefSeq, Jul 2008]

ITGAE 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=0.0019013882).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002208.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITGAE	NM_002208.5	MANE Select	c.2676G>C	p.Gln892His	missense	Exon 22 of 31	NP_002199.3
ITGAE	NM_001425071.1		c.2676G>C	p.Gln892His	missense	Exon 22 of 30	NP_001412000.1
ITGAE	NM_001425072.1		c.2676G>C	p.Gln892His	missense	Exon 22 of 29	NP_001412001.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITGAE	ENST00000263087.9	TSL:1 MANE Select	c.2676G>C	p.Gln892His	missense	Exon 22 of 31	ENSP00000263087.4
ITGAE	ENST00000571185.1	TSL:3	n.247G>C		non_coding_transcript_exon	Exon 3 of 7
ITGAE	ENST00000574026.2	TSL:3	c.259-1263G>C		intron	N/A	ENSP00000467977.1

Frequencies

GnomAD3 genomes

AF:

0.0805

AC:

12244

AN:

152146

Hom.:

673

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.168

Gnomad ASJ

AF:

0.0982

Gnomad EAS

AF:

0.0310

Gnomad SAS

AF:

0.0364

Gnomad FIN

AF:

0.0779

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0530

Gnomad OTH

AF:

0.0842

GnomAD2 exomes

AF:

0.0796

AC:

20003

AN:

251448

AF XY:

0.0712

show subpopulations

Gnomad AFR exome

AF:

0.107

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.0993

Gnomad EAS exome

AF:

0.0284

Gnomad FIN exome

AF:

0.0765

Gnomad NFE exome

AF:

0.0529

Gnomad OTH exome

AF:

0.0761

GnomAD4 exome

AF:

0.0575

AC:

84072

AN:

1461364

Hom.:

3338

Cov.:

AF XY:

0.0559

AC XY:

40675

AN XY:

727046

show subpopulations

African (AFR)

AF:

0.111

AC:

3710

AN:

33462

American (AMR)

AF:

0.216

AC:

9670

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

2701

AN:

26124

East Asian (EAS)

AF:

0.0268

AC:

1062

AN:

39698

South Asian (SAS)

AF:

0.0354

AC:

3053

AN:

86250

European-Finnish (FIN)

AF:

0.0750

AC:

4004

AN:

53412

Middle Eastern (MID)

AF:

0.0612

AC:

353

AN:

5764

European-Non Finnish (NFE)

AF:

0.0501

AC:

55654

AN:

1111552

Other (OTH)

AF:

0.0640

AC:

3865

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

3807

7613

11420

15226

19033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2220

4440

6660

8880

11100

<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:

0.0805

AC:

12254

AN:

152264

Hom.:

674

Cov.:

AF XY:

0.0813

AC XY:

6049

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.104

AC:

4314

AN:

41536

American (AMR)

AF:

0.169

AC:

2578

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0982

AC:

341

AN:

3472

East Asian (EAS)

AF:

0.0306

AC:

159

AN:

5188

South Asian (SAS)

AF:

0.0364

AC:

176

AN:

4832

European-Finnish (FIN)

AF:

0.0779

AC:

826

AN:

10598

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0530

AC:

3604

AN:

68026

Other (OTH)

AF:

0.0838

AC:

177

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

580

1159

1739

2318

2898

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0521

Hom.:

208

Bravo

AF:

0.0893

TwinsUK

AF:

0.0437

AC:

162

ALSPAC

AF:

0.0426

AC:

164

ESP6500AA

AF:

0.0962

AC:

424

ESP6500EA

AF:

0.0526

AC:

452

ExAC

AF:

0.0732

AC:

8890

Asia WGS

AF:

0.0460

AC:

160

AN:

3478

EpiCase

AF:

0.0547

EpiControl

AF:

0.0550

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.078

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PhyloP100

0.80

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.13

Sift

Benign

0.036

Sift4G

Uncertain

0.056

Polyphen

0.99

Vest4

0.059

MutPred

0.28

Loss of sheet (P = 0.0817)

MPC

0.25

ClinPred

0.017

GERP RS

5.1

Varity_R

0.30

gMVP

0.28

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over