rs149468422

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS3BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000419.4:c.2614C>A variant that results in the Leu872Met amino acid change is reported at frequencies (2%; 0.02101 in the African subpopulation, with 5 homozygotes, in gnomAD) higher than the recommended threshold of 0.24%, in population databases. The variant is not reported in any GT patients in the literature. Experimental evidence suggests no impact to expression or function of the αIIbβ3 complex. Computation evidence also suggests no impact with a REVEL score of 0.136. In summary, based on the available evidence, the Leu872Met variant is classified as "benign". GT-specific criteria applied: BA1, BS3, and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8602631/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.0060 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 12 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: -0.253

Publications

3 publications found

Variant links:

Genes affected

ITGA2B (HGNC:6138): (integrin subunit alpha 2b) This gene encodes a member of the integrin alpha chain family of proteins. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate through disulfide linkages to form a subunit of the alpha-IIb/beta-3 integrin cell adhesion receptor. This receptor plays a crucial role in the blood coagulation system, by mediating platelet aggregation. Mutations in this gene are associated with platelet-type bleeding disorders, which are characterized by a failure of platelet aggregation, including Glanzmann thrombasthenia. [provided by RefSeq, Jan 2016]

ITGA2B Gene-Disease associations (from GenCC):

platelet-type bleeding disorder 16
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Glanzmann thrombasthenia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Glanzmann's thrombasthenia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
Glanzmann thrombasthenia 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ITGA2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2B	NM_000419.5 link	c.2614C>A	p.Leu872Met	missense_variant	Exon 26 of 30	ENST00000262407.6	NP_000410.2	P08514-1
ITGA2B	XM_011524749.2 link	c.2767C>A	p.Leu923Met	missense_variant	Exon 26 of 29		XP_011523051.2	P08514
ITGA2B	XM_011524750.2 link	c.2767C>A	p.Leu923Met	missense_variant	Exon 26 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITGA2B	ENST00000262407.6 link	c.2614C>A	p.Leu872Met	missense_variant	Exon 26 of 30	1	NM_000419.5	ENSP00000262407.5	P08514-1
ITGA2B	ENST00000648408.1 link	c.2044C>A	p.Leu682Met	missense_variant	Exon 22 of 25			ENSP00000498119.1	A0A3B3IU79
ITGA2B	ENST00000592462.5 link	n.1409C>A		non_coding_transcript_exon_variant	Exon 15 of 15	5
ITGA2B	ENST00000587295.5 link	c.252+129C>A		intron_variant	Intron 2 of 2	3		ENSP00000467269.1	K7EP83

Frequencies

GnomAD3 genomes

AF:

0.00602

AC:

916

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0211

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00147

AC:

290

AN:

197460

AF XY:

0.000976

show subpopulations

Gnomad AFR exome

AF:

0.0217

Gnomad AMR exome

AF:

0.000617

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000129

Gnomad OTH exome

AF:

0.000587

GnomAD4 exome

AF:

0.000697

AC:

999

AN:

1433504

Hom.:

Cov.:

AF XY:

0.000616

AC XY:

438

AN XY:

710768

show subpopulations

African (AFR)

AF:

0.0221

AC:

733

AN:

33202

American (AMR)

AF:

0.000825

AC:

AN:

38804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25474

East Asian (EAS)

AF:

0.00

AC:

AN:

38658

South Asian (SAS)

AF:

0.0000603

AC:

AN:

82862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51134

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.000129

AC:

142

AN:

1098262

Other (OTH)

AF:

0.00143

AC:

AN:

59396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00605

AC:

921

AN:

152280

Hom.:

Cov.:

AF XY:

0.00568

AC XY:

423

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0211

AC:

878

AN:

41564

American (AMR)

AF:

0.00131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

67996

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00317

Hom.:

Bravo

AF:

0.00685

ESP6500AA

AF:

0.0196

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00153

AC:

183

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Benign:3

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jun 04, 2020

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000419.4:c.2614C>A variant that results in the Leu872Met amino acid change is reported at frequencies (2%; 0.02101 in the African subpopulation, with 5 homozygotes, in gnomAD) higher than the recommended threshold of 0.24%, in population databases. The variant is not reported in any GT patients in the literature. Experimental evidence suggests no impact to expression or function of the Î±IIbÎ²3 complex. Computation evidence also suggests no impact with a REVEL score of 0.136. In summary, based on the available evidence, the Leu872Met variant is classified as "benign". GT-specific criteria applied: BA1, BS3, and BP4. -

not specified

Benign:1

Jun 10, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.090

Eigen

Benign

-0.030

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.6

PhyloP100

-0.25

PrimateAI

Benign

0.27

PROVEAN

Benign

0.33

REVEL

Benign

0.14

Sift

Benign

0.16

Sift4G

Benign

0.17

Polyphen

0.90

Vest4

0.11

MVP

0.43

MPC

0.74

ClinPred

0.022

GERP RS

3.4

PromoterAI

-0.0017

Neutral

(source)

Varity_R

0.20

gMVP

0.27

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over