rs79775494

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000212.3(ITGB3):c.836A>T(p.Lys279Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:2

Conservation

PhyloP100: 1.81

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000212.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB3	NM_000212.3 linkuse as main transcript	c.836A>T	p.Lys279Met	missense_variant	6/15	ENST00000559488.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB3	ENST00000559488.7 linkuse as main transcript	c.836A>T	p.Lys279Met	missense_variant	6/15	1	NM_000212.3	P1	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.836A>T	p.Lys279Met	missense_variant	6/9	1
ITGB3	ENST00000696963.1 linkuse as main transcript	c.836A>T	p.Lys279Met	missense_variant	6/14				P05106-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251402

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00000137

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2010

- -

Glanzmann thrombasthenia

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Aug 17, 2021

The ITGB3 missense variant NM_000212.3:c.836A>T replaces the lysine residue with a methionine residue (p.Lys279Met) and is absent from control population databases. The variant is predicted by in silico tools to be damaging to protein function. The functional impact has been assessed by flow cytometric detection of Î±IIb, Î²3, and Î±IIbÎ²3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number cells positive for the Î±IIbÎ²3 complex (estimated to be ~7% compared to wild type; PMID: 20020534). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-24 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and the second ITGB3 variant identified in the individual is of uncertain significance and unknown phase. In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 13568). This missense change has been observed in individual(s) with Glanzmann thrombasthenia (PMID: 20020534). This variant is present in population databases (rs79775494, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 279 of the ITGB3 protein (p.Lys279Met). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.30

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.83

N;.

Sift

Benign

0.089

T;.

Sift4G

Benign

0.11

T;T

Polyphen

0.98

D;.

Vest4

0.79

MutPred

0.83

Loss of catalytic residue at K279 (P = 5e-04);Loss of catalytic residue at K279 (P = 5e-04);

MVP

0.98

MPC

1.4

ClinPred

0.70

GERP RS

2.8

Varity_R

0.30

gMVP

0.82

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