rs78657866

Positions:

chr17-44374470-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS2PM3PP3PM2_SupportingPS3_ModeratePP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.2944G>A (p.Val982Met) missense variant has been reported in at least three compound heterozygous probands with a phenotype highly specific to GT (PMID:28983057, 25539746,15099289); one of which was a de novo occurrence (PMID:25539746). It is found at an extremely low frequency (MAF of 0.00006486 in the non-Finnish European population from gnomAD). This variant is predicted by HSF and MaxEntScan to result in a broken splice donor site. Flow cytometry found that this variant had a marked deleterious effect on αIIbβ3 expression (~25% of control levels) in COS-7 cells (PMID:15099289). In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS2, PM3, PM2_supporting, PS3_Moderate, PP3, and PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16608466/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 missense, splice_region

Scores

11

8

Splicing: ADA: 0.9997

2

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 2.45

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:

ITGA2B (HGNC:):

ITGA2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS2

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

PS3

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

PM2

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

PM3

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

PP3

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

PP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA2B	NM_000419.5 linkuse as main transcript	c.2944G>A	p.Val982Met	missense_variant, splice_region_variant	29/30	ENST00000262407.6	NP_000410.2	P08514-1
ITGA2B	XM_011524749.2 linkuse as main transcript	c.2995G>A	p.Val999Met	missense_variant, splice_region_variant	28/29		XP_011523051.2	P08514
ITGA2B	XM_011524750.2 linkuse as main transcript	c.3096+189G>A		intron_variant			XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6 linkuse as main transcript	c.2944G>A	p.Val982Met	missense_variant, splice_region_variant	29/30	1	NM_000419.5	ENSP00000262407.5		P08514-1
ITGA2B	ENST00000648408.1 linkuse as main transcript	c.2373+189G>A		intron_variant				ENSP00000498119.1		A0A3B3IU79
ITGA2B	ENST00000587295.5 linkuse as main transcript	c.252+1363G>A		intron_variant		3		ENSP00000467269.1		K7EP83
ITGA2B	ENST00000592462.5 linkuse as main transcript	n.2643G>A		non_coding_transcript_exon_variant	15/15	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152178

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

5

AN:

1461518

Hom.:

0

Cov.:

31

AF XY:

0.00000413

AC XY:

3

AN XY:

727102

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152178

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Sep 06, 2020

The c.2944G>A (p.Val982Met) missense variant has been reported in at least three compound heterozygous probands with a phenotype highly specific to GT (PMID: 28983057, 25539746,15099289); one of which was a de novo occurrence (PMID: 25539746). It is found at an extremely low frequency (MAF of 0.00006486 in the non-Finnish European population from gnomAD). This variant is predicted by HSF and MaxEntScan to result in a broken splice donor site. Flow cytometry found that this variant had a marked deleterious effect on Î±IIbÎ²3 expression (~25% of control levels) in COS-7 cells (PMID: 15099289). In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS2, PM3, PM2_supporting, PS3_Moderate, PP3, and PP4_moderate. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 27, 2016

The V982M variant in the ITGA2B gene has been reported previously (as V951M due to the use of alternate nomenclature) in assocation with Glanzmann thrombasthenia (Nurden et al., 2004; Jallu et al., 2010). In one individual, V982M was identified in the compound heterozygous state with a splice site variant (Nurden et al., 2004), while in another individual, no second pathogenic variant was identified (Jallu et al., 2010). The V982M variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V982M variant is a conservative amino acid substitution, which occurs at a position that is conserved in mammals. Functional studies demonstrate that V982M results in significant loss of ITGA2b protein surface expression (Nurden et al., 2004). The V982M variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Glanzmann thrombasthenia 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.15

D

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.89

D

LIST_S2

Benign

0.82

T

M_CAP

Benign

0.040

D

MetaRNN

Uncertain

0.65

D

MetaSVM

Benign

-0.36

T

MutationAssessor

Uncertain

2.2

M

PrimateAI

Uncertain

0.72

T

PROVEAN

Benign

-1.7

N

REVEL

Uncertain

0.33

Sift

Benign

0.089

T

Sift4G

Benign

0.16

T

Polyphen

1.0

D

Vest4

0.35

MutPred

0.77

Loss of sheet (P = 0.0817);

MVP

0.77

MPC

0.97

ClinPred

0.94

D

GERP RS

5.0

Varity_R

0.24

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.19

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.

Other links and lift over

dbSNP: rs78657866; hg19: chr17-42451838;