17-44372385-T-A

Position:

chr17-44372385-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The missense variant c.3099A>T (p.Glu1033Asp) has been reported heterozygous in one patient (PMID:31064749) however a second variant was not identified. Communication with the authors confirmed the patient had decreased platelet glycoprotein IIb-IIIa, abnormal bleeding, and impaired platelet aggregation with ADP, epinephrine, arachidonic acid, and collagen. The highest population minor allele frequency in gnomAD v4.0.0 is 0.00003334 (2/59980 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Computational predictors agree that this variant does not have a deleterious effect (REVEL score of 0.193; BP4). In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PM2_supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA290942825/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3

Conservation

PhyloP100: 0.0330

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

BP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ITGA2B	NM_000419.5 linkuse as main transcript	c.3099A>T	p.Glu1033Asp	missense_variant	30/30	ENST00000262407.6
ITGA2B	XM_011524749.2 linkuse as main transcript	c.3150A>T	p.Glu1050Asp	missense_variant	29/29
ITGA2B	XM_011524750.2 linkuse as main transcript	c.3135A>T	p.Glu1045Asp	missense_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6 linkuse as main transcript	c.3099A>T	p.Glu1033Asp	missense_variant	30/30	1	NM_000419.5	P1	P08514-1
ITGA2B	ENST00000648408.1 linkuse as main transcript	c.2415A>T	p.Glu805Asp	missense_variant	25/25
ITGA2B	ENST00000587295.5 linkuse as main transcript	c.294A>T	p.Glu98Asp	missense_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	May 02, 2024	The missense variant c.3099A>T (p.Glu1033Asp) has been reported heterozygous in one patient (PMID: 31064749) however a second variant was not identified. Communication with the authors confirmed the patient had decreased platelet glycoprotein IIb-IIIa, abnormal bleeding, and impaired platelet aggregation with ADP, epinephrine, arachidonic acid, and collagen. The highest population minor allele frequency in gnomAD v4.0.0 is 0.00003334 (2/59980 alleles) in the Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). Computational predictors agree that this variant does not have a deleterious effect (REVEL score of 0.193; BP4). In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PM2_supporting, BP4. -

ITGA2B-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 09, 2023

The ITGA2B c.3099A>T variant is predicted to result in the amino acid substitution p.Glu1033Asp. This variant was reported in an individual with platelet function disorder (Supplementary File 3 in Downes et al. 2019. PubMed ID: 31064749). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is reported as a variant of uncertain significance in ClinVar by the ClinGen Platelet Disorders Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/627299/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Benign

9.4

DANN

Benign

0.87

DEOGEN2

Benign

0.27

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.39

M_CAP

Benign

0.033

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.70

N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

0.070

REVEL

Benign

0.19

Sift

Benign

1.0

Sift4G

Benign

0.75

Polyphen

0.0060

Vest4

0.13

MutPred

0.42

Gain of loop (P = 0.0166);

MVP

0.46

MPC

0.27

ClinPred

0.062

GERP RS

-1.5

Varity_R

0.044

gMVP

0.37

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