rs121918444

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM3PP4_ModeratePP3PM2_SupportingPS3

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
NM_000212.3 missense

Scores

8

6

4

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 8.00

Publications

13 publications found

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:

EFCAB13-DT (HGNC:55338): (EFCAB13 divergent transcript)

EFCAB13-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
ITGB3	NM_000212.3 link	c.719G>A	p.Arg240Gln	missense_variant	Exon 5 of 15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7 link	c.719G>A	p.Arg240Gln	missense_variant	Exon 5 of 15	1	NM_000212.3	ENSP00000452786.2
ENSG00000259753	ENST00000560629.1 link	n.683G>A		non_coding_transcript_exon_variant	Exon 5 of 18	2		ENSP00000456711.2

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

African (AFR)

AF:

0.00

AC:

0

AN:

33480

American (AMR)

AF:

0.00

AC:

0

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

1

AN:

1112006

Other (OTH)

AF:

0.00

AC:

0

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

African (AFR)

AF:

0.00

AC:

0

AN:

41442

American (AMR)

AF:

0.00

AC:

0

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

68032

Other (OTH)

AF:

0.000479

AC:

1

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Bleeding disorder, platelet-type, 24

Pathogenic:1

Mar 21, 2022

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Glanzmann thrombasthenia

Pathogenic:1

Jul 08, 2021

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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

Feb 25, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Platelet-type bleeding disorder 16

Pathogenic:1

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

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

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

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;For recessive disorders, detected in trans with a pathogenic variant.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

not provided

Pathogenic:1

Feb 23, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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;.

PhyloP100

8.0

PrimateAI

Uncertain

0.61

T

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.0

Sift

Benign

0.20

T;.

Sift4G

Benign

0.23

T;T

Vest4

0.77

ClinPred

0.99

D

GERP RS

4.7

Varity_R

0.73

gMVP

0.82

Mutation Taster

=6/94

disease causing (ClinVar)

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

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Other links and lift over

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