rs121918446

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3PM5PP4_ModeratePP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp) missense variant has been reported in at least five patients (PMID:32200672, 7509233, 1602006, doi.org/10.2491/jjsth.10.243, and a thesis by Zapelli in 2014) with a phenotype highly specific to GT. Several probands from PMID:32200672, PMID:7509233, and PMID:1602006 are homozygous (PM3) and meet the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, surface αIIbβ3 was dysfunctional as shown by defective PAC-1 and fibrinogen binding. This variant is at an extremely low frequency (below the <1/10,000 threshold) with a MAF of 0.00002196 (2/91,084 alleles) in the gnomADv4.1.0 South Asian population (PM2_supporting). It is predicted to have a deleterious effect (REVEL score 0.832; PP3) and occurs at the same residue as pathogenic variant Arg240Gln (PM5). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM5, PP3, and PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA123228/MONDO:0100326/011

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

9

7

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 2.17

Publications

8 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

Specifications for ITGB3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

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

PM3

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

PM5

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000212.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	NM_000212.3	MANE Select	c.718C>T	p.Arg240Trp	missense	Exon 5 of 15	NP_000203.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	ENST00000559488.7	TSL:1 MANE Select	c.718C>T	p.Arg240Trp	missense	Exon 5 of 15	ENSP00000452786.2	P05106-1
	ITGB3	ENST00000571680.1	TSL:1	c.718C>T	p.Arg240Trp	missense	Exon 5 of 9	ENSP00000461626.1	I3L4X8
	ENSG00000259753	ENST00000560629.1	TSL:2	n.682C>T		non_coding_transcript_exon	Exon 5 of 18	ENSP00000456711.2	H3BM21

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152160

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

3

AN:

249030

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

3

AN:

1461880

Hom.:

0

Cov.:

32

AF XY:

0.00000275

AC XY:

2

AN XY:

727242

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:

39698

South Asian (SAS)

AF:

0.0000232

AC:

2

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

1

AN:

1112004

Other (OTH)

AF:

0.00

AC:

0

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

152160

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41444

American (AMR)

AF:

0.00

AC:

0

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

1

AN:

68038

Other (OTH)

AF:

0.00

AC:

0

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Genome 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

Alfa

AF:

0.0000188

Hom.:

0

ExAC

AF:

0.0000165

AC:

2

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

2

-

-

Glanzmann thrombasthenia (2)

2

-

-

Glanzmann thrombasthenia 2 (2)

1

-

-

Glanzmann thrombasthenia 1 (1)

1

-

-

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.39

D

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

32

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.69

D

LIST_S2

Pathogenic

0.98

D

M_CAP

Uncertain

0.14

D

MetaRNN

Pathogenic

0.96

D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.0

M

PhyloP100

2.2

PrimateAI

Uncertain

0.74

T

PROVEAN

Uncertain

-4.2

D

Sift

Uncertain

0.020

D

Sift4G

Uncertain

0.020

D

Polyphen

1.0

D

Vest4

0.81

MutPred

0.91

Loss of disorder (P = 0.0153)

MVP

0.99

MPC

1.3

ClinPred

0.99

D

GERP RS

3.7

Varity_R

0.79

gMVP

0.88

Mutation Taster

=13/87

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: rs121918446; hg19: chr17-45363729; API