17-47283544-G-A

Position:

chr17-47283544-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP4_StrongPP3

This summary comes from the ClinGen Evidence Repository: The NM_000212.3(ITGB3):c.356G>A variant predicts a missense change, Arg119Gln. It is reported at a frequency of 0.0001468 (11/74914 alleles) in the gnomAD v4.0.0 African/African-American population, above the <0.0001 threshold for PM2_Supporting. At least 4 GT patients (homozygous and compound heterozygous) with the variant have been reported in the literature (PMIDs: 19691478, 16463284, 25728920). The proband from PMID:25728920 meets criteria for PP4_Strong including bleeding phenotype, abnormal platelet aggregation in response to >2 agonists and normal aggregation to ristocetin, reduced αIIbβ3 integrin expression on flow cytometry and full sequencing of ITGA2B and ITGB3 both genes. The variant has a REVEL score of 0.936, meeting criteria for PP3 (threshold: >0.7). In summary, there is insufficient evidence at this time to classify the Arg119Gln variant. GT-specific criteria met: PP3, PP4_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8622925/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:1

Conservation

PhyloP100: 9.42

Variant links:

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

ITGB3 links:

ENSG00000259753 (HGNC:):

ENSG00000259753 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

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
ITGB3	NM_000212.3 linkuse as main transcript	c.356G>A	p.Arg119Gln	missense_variant	3/15	ENST00000559488.7	NP_000203.2	P05106-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ITGB3	ENST00000559488.7 linkuse as main transcript	c.356G>A	p.Arg119Gln	missense_variant	3/15	1	NM_000212.3	ENSP00000452786.2	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.356G>A	p.Arg119Gln	missense_variant	3/9	1		ENSP00000461626.1	I3L4X8
ENSG00000259753	ENST00000560629.1 linkuse as main transcript	n.320G>A		non_coding_transcript_exon_variant	3/18	2		ENSP00000456711.2	H3BM21
ITGB3	ENST00000696963.1 linkuse as main transcript	c.356G>A	p.Arg119Gln	missense_variant	3/14			ENSP00000513002.1	P05106-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249610

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135108

show subpopulations

Gnomad AFR exome

AF:

0.000247

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000187

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 119 of the ITGB3 protein (p.Arg119Gln). This variant is present in population databases (rs147782061, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive Glanzmann thrombasthenia (PMID: 16463284, 19691478, 25728920). ClinVar contains an entry for this variant (Variation ID: 996208). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ITGB3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Glanzmann thrombasthenia

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Nov 02, 2023

The NM_000212.3(ITGB3):c.356G>A variant predicts a missense change, Arg119Gln. It is reported at a frequency of 0.0001468 (11/74914 alleles) in the gnomAD v4.0.0 African/African-American population, above the <0.0001 threshold for PM2_Supporting. At least 4 GT patients (homozygous and compound heterozygous) with the variant have been reported in the literature (PMIDs: 19691478, 16463284, 25728920). The proband from PMID: 25728920 meets criteria for PP4_Strong including bleeding phenotype, abnormal platelet aggregation in response to >2 agonists and normal aggregation to ristocetin, reduced αIIbβ3 integrin expression on flow cytometry and full sequencing of ITGA2B and ITGB3 both genes. The variant has a REVEL score of 0.936, meeting criteria for PP3 (threshold: >0.7). In summary, there is insufficient evidence at this time to classify the Arg119Gln variant. GT-specific criteria met: PP3, PP4_strong. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

H;.

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.8

D;.

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.016

D;D

Polyphen

0.98

D;.

Vest4

0.92

MVP

0.98

MPC

1.3

ClinPred

1.0

GERP RS

5.9

Varity_R

0.77

gMVP

0.87

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