chr17-47283375-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP4_StrongPP3PM2_SupportingPS3_ModeratePM3_Supporting

This summary comes from the ClinGen Evidence Repository: The missense variant, NM_000212.3(ITGB3):c.187C>T (p.Arg63Cys), has been reported in one compound heterozygous proband (PMID:25728920) with Pathogenic variant NM_000212.2:c.505C>T Arg169Ter (PM3_supporting). The patient (GT7 in PMID:25728920/Case 2 in PMID:35286390) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 15% (<25%), as measured by flow cytometry (PP4_strong). It occurs at an extremely low frequency, with an overall allele frequency in gnomAD of 0.00002476 (MAF of 0.00005012 in the East Asian population; PM2_supporting). It is predicted damaging by in-silico tools (REVEL score of 0.98; PP3). In transiently transfected COS‐7 cells expressing Arg63Cys mutant integrin FACS analysis showed 85% reduction of αIIbβ3Cys63 expression (PS3_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PP3, PS3_moderate (VCEP specifications version 2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8622892/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

15

2

Clinical Significance

Likely pathogenic reviewed by expert panel P:1U:1

Conservation

PhyloP100: 7.71

Publications

4 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: Likely_pathogenic. The variant received 9 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.

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.187C>T	p.Arg63Cys	missense	Exon 3 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.187C>T	p.Arg63Cys	missense	Exon 3 of 15	ENSP00000452786.2	P05106-1
	ITGB3	ENST00000571680.1	TSL:1	c.187C>T	p.Arg63Cys	missense	Exon 3 of 9	ENSP00000461626.1	I3L4X8
	ENSG00000259753	ENST00000560629.1	TSL:2	n.151C>T		non_coding_transcript_exon	Exon 3 of 18	ENSP00000456711.2	H3BM21

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

3

AN:

152230

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

5

AN:

251276

AF XY:

0.0000221

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

43

AN:

1461882

Hom.:

0

Cov.:

33

AF XY:

0.0000330

AC XY:

24

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000597

AC:

2

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:

0.0000252

AC:

1

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86254

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:

0.0000333

AC:

37

AN:

1112008

Other (OTH)

AF:

0.0000497

AC:

3

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0

3

6

9

12

15

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:

0.0000197

AC:

3

AN:

152230

Hom.:

0

Cov.:

32

AF XY:

0.0000269

AC XY:

2

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41460

American (AMR)

AF:

0.00

AC:

0

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

3

AN:

68042

Other (OTH)

AF:

0.00

AC:

0

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

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:

0.0000712

Hom.:

0

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

4

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

1

-

-

Glanzmann thrombasthenia (1)

-

1

-

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

31

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

1.0

D

LIST_S2

Uncertain

0.95

D

M_CAP

Pathogenic

0.62

D

MetaRNN

Pathogenic

0.99

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.9

H

PhyloP100

7.7

PrimateAI

Uncertain

0.54

T

PROVEAN

Pathogenic

-6.8

D

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.95

MutPred

0.91

Gain of catalytic residue at P62 (P = 0.0074)

MVP

0.99

MPC

1.5

ClinPred

1.0

D

GERP RS

5.9

Varity_R

0.79

gMVP

0.99

Mutation Taster

=2/98

disease causing (ClinVar)

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

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Other links and lift over

dbSNP: rs199866795; hg19: chr17-45360741; COSMIC: COSV71383286; COSMIC: COSV71383286; API