rs121918444

Positions:

chr17-47286364-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3PM3PP4_ModeratePP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000212.2(ITGB3):c.719G>A (p.Arg240Gln) missense variant has been reported in at least four patients (PMIDs: 1371279, 29084015, 29675921, 30138987) with a phenotype highly specific to GT. This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP and is predicted to have a deleterious effect (REVEL score 0.819). The functional impact has been assessed by transfection in CHO cells, showing normal αIIbβ3 surface expression with a deficiency in binding of fibrinogen and PAC-1 in response to mAb 62 stimulation (PMID:1371279). In summary this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS3, PM2_Supporting, PM3, PP3, and PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA123224/MONDO:0100326/011

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITGB3
ENST00000559488.7 missense

Scores

8

6

4

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 8.00

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 Pathogenic. Variant got 10 ACMG points.

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
ITGB3	NM_000212.3 linkuse as main transcript	c.719G>A	p.Arg240Gln	missense_variant	5/15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7 linkuse as main transcript	c.719G>A	p.Arg240Gln	missense_variant	5/15	1	NM_000212.3	ENSP00000452786	P1	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.719G>A	p.Arg240Gln	missense_variant	5/9	1		ENSP00000461626
ITGB3	ENST00000696963.1 linkuse as main transcript	c.719G>A	p.Arg240Gln	missense_variant	5/14			ENSP00000513002		P05106-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152166

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461882

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

727244

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152166

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74340

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:

0.00

Gnomad4 OTH

AF:

0.000479

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

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

Jul 08, 2021

The NM_000212.2(ITGB3):c.719G>A (p.Arg240Gln) missense variant has been reported in at least four patients (PMIDs: 1371279, 29084015, 29675921, 30138987) with a phenotype highly specific to GT. This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP and is predicted to have a deleterious effect (REVEL score 0.819). The functional impact has been assessed by transfection in CHO cells, showing normal Î±IIbÎ²3 surface expression with a deficiency in binding of fibrinogen and PAC-1 in response to mAb 62 stimulation (PMID: 1371279). In summary this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS3, PM2_Supporting, PM3, PP3, and PP4_Moderate. -

Glanzmann thrombasthenia 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 25, 1992

- -

Platelet-type bleeding disorder 16

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

-

- -

Myocardial infarction, susceptibility to;C5543273:Glanzmann thrombasthenia 2;C5543280:Bleeding disorder, platelet-type, 24

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PP3+PP4_Moderate+PM3+PS3 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.53

D

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

33

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

D;.

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.91

D

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.15

D

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.0

M;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.61

T

PROVEAN

Benign

-1.9

N;.

Sift

Benign

0.20

T;.

Sift4G

Benign

0.23

T;T

Polyphen

1.0

D;.

Vest4

0.77

MutPred

0.92

Gain of ubiquitination at K235 (P = 0.0369);Gain of ubiquitination at K235 (P = 0.0369);

MVP

0.98

MPC

1.3

ClinPred

0.99

D

GERP RS

4.7

Varity_R

0.73

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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: rs121918444; hg19: chr17-45363730; COSMIC: COSV71384179; COSMIC: COSV71384179;