rs149468422

Positions:

chr17-44375704-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

BS3

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ITGA2B	NM_000419.5 linkuse as main transcript	c.2614C>A	p.Leu872Met	missense_variant	26/30	ENST00000262407.6
ITGA2B	XM_011524749.2 linkuse as main transcript	c.2767C>A	p.Leu923Met	missense_variant	26/29
ITGA2B	XM_011524750.2 linkuse as main transcript	c.2767C>A	p.Leu923Met	missense_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6 linkuse as main transcript	c.2614C>A	p.Leu872Met	missense_variant	26/30	1	NM_000419.5	P1	P08514-1
ITGA2B	ENST00000648408.1 linkuse as main transcript	c.2047C>A	p.Leu683Met	missense_variant	22/25
ITGA2B	ENST00000587295.5 linkuse as main transcript	c.253+129C>A		intron_variant		3
ITGA2B	ENST00000592462.5 linkuse as main transcript	n.1409C>A		non_coding_transcript_exon_variant	15/15	5

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

GnomAD3 exomes

AF:

0.00147

AC:

290

AN:

197460

Hom.:

AF XY:

0.000976

AC XY:

104

AN XY:

106604

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 SAS exome

AF:

0.0000379

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

Gnomad4 AFR exome

AF:

0.0221

Gnomad4 AMR exome

AF:

0.000825

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000603

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.00143

GnomAD4 genome

AF:

0.00605

AC:

921

AN:

152280

Hom.:

Cov.:

AF XY:

0.00568

AC XY:

423

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0211

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00473

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Jun 04, 2020	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

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 10, 2020

- -

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

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

MutationTaster

Benign

1.0

N;N

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

Varity_R

0.20

gMVP

0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over