chr17-44374352-A-G

Position:

chr17-44374352-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_SupportingPVS1_StrongPP4_StrongPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.4:c.3060+2T>C variant is a splice site variant that causes aberrant splicing and results in the deletion of 38 amino acids in the transmembrane domain (PMID:9215749). It is present in a very low frequency in gnomAD (0.00003876). It is seen in four individuals in the compound heterozygous state in the published literature. In summary, based on the available evidence at the time the c.3060+2T>C variant is classified as pathogenic. GT-specific criteria applied: PVS1_Strong, PM2_Supporting, PP4_Strong, PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA290944108/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

ITGA2B
NM_000419.5 splice_donor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic reviewed by expert panel P:4U:1

Conservation

PhyloP100: 4.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

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.

PP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ITGA2B	NM_000419.5 linkuse as main transcript	c.3060+2T>C	splice_donor_variant	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2 linkuse as main transcript	c.3111+2T>C	splice_donor_variant		XP_011523051.2
ITGA2B	XM_011524750.2 linkuse as main transcript	c.3096+307T>C	intron_variant		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6 linkuse as main transcript	c.3060+2T>C	splice_donor_variant		1	NM_000419.5	ENSP00000262407	P1	P08514-1
ITGA2B	ENST00000587295.5 linkuse as main transcript	c.253+1481T>C	intron_variant		3		ENSP00000467269
ITGA2B	ENST00000648408.1 linkuse as main transcript	c.2374+307T>C	intron_variant				ENSP00000498119
ITGA2B	ENST00000592462.5 linkuse as main transcript	n.2761T>C	non_coding_transcript_exon_variant	15/15	5

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151810

Hom.:

Cov.:

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:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251324

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461414

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727064

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151810

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74132

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:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000970

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Glanzmann thrombasthenia

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Sep 04, 2020

The NM_000419.4:c.3060+2T>C variant is a splice site variant that causes aberrant splicing and results in the deletion of 38 amino acids in the transmembrane domain (PMID: 9215749). It is present in a very low frequency in gnomAD (0.00003876). It is seen in four individuals in the compound heterozygous state in the published literature. In summary, based on the available evidence at the time the c.3060+2T>C variant is classified as pathogenic. GT-specific criteria applied: PVS1_Strong, PM2_Supporting, PP4_Strong, PM3_Supporting. -

Glanzmann thrombasthenia 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KardioGenetik, Herz- und Diabeteszentrum NRW

Aug 15, 2023

- -

Abnormal platelet function

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Benign

0.68

MutationTaster

Benign

1.0

A;A

GERP RS

5.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.76

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.76

Position offset: 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