17-47292411-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.1533A>G (p.Glu511=), no individuals with Glanzmann thrombasthenia were reported with the variant. Moreover, the variant has a minor allele frequency of 0.3455 (6891/19944) in gnomAD, found in the East Asian population, which is considerably higher than the expected frequency of the disease (BA1). In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4 (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8623279/MONDO:0100326/011

Frequency

Genomes: 𝑓 0.29 ( 6393 hom., cov: 33)

Exomes 𝑓: 0.29 ( 61592 hom. )

Consequence

ITGB3
NM_000212.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 2.13

Publications

33 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: Benign. The variant received -9 ACMG points.

BP4

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

BA1

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.1533A>G	p.Glu511Glu	synonymous_variant	Exon 10 of 15	ENST00000559488.7	NP_000203.2	P05106-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7 link	c.1533A>G	p.Glu511Glu	synonymous_variant	Exon 10 of 15	1	NM_000212.3	ENSP00000452786.2		P05106-1
ENSG00000259753	ENST00000560629.1 link	n.1497A>G		non_coding_transcript_exon_variant	Exon 10 of 18	2		ENSP00000456711.2		H3BM21

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43526

AN:

152034

Hom.:

6383

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.266

Gnomad AMR

AF:

0.280

Gnomad ASJ

AF:

0.282

Gnomad EAS

AF:

0.332

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.283

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.297

Gnomad OTH

AF:

0.306

GnomAD2 exomes

AF:

0.286

AC:

71739

AN:

250598

AF XY:

0.289

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.230

Gnomad ASJ exome

AF:

0.290

Gnomad EAS exome

AF:

0.345

Gnomad FIN exome

AF:

0.291

Gnomad NFE exome

AF:

0.294

Gnomad OTH exome

AF:

0.292

GnomAD4 exome

AF:

0.289

AC:

422482

AN:

1460006

Hom.:

61592

Cov.:

AF XY:

0.289

AC XY:

210104

AN XY:

725966

show subpopulations

African (AFR)

AF:

0.274

AC:

9154

AN:

33442

American (AMR)

AF:

0.235

AC:

10515

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

7526

AN:

26102

East Asian (EAS)

AF:

0.341

AC:

13541

AN:

39658

South Asian (SAS)

AF:

0.294

AC:

25348

AN:

86232

European-Finnish (FIN)

AF:

0.291

AC:

15512

AN:

53316

Middle Eastern (MID)

AF:

0.300

AC:

1727

AN:

5760

European-Non Finnish (NFE)

AF:

0.290

AC:

321511

AN:

1110502

Other (OTH)

AF:

0.293

AC:

17648

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

17773

35546

53320

71093

88866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10622

21244

31866

42488

53110

<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:

0.286

AC:

43560

AN:

152154

Hom.:

6393

Cov.:

AF XY:

0.285

AC XY:

21232

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.265

AC:

11006

AN:

41500

American (AMR)

AF:

0.280

AC:

4279

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

979

AN:

3472

East Asian (EAS)

AF:

0.333

AC:

1721

AN:

5174

South Asian (SAS)

AF:

0.294

AC:

1417

AN:

4822

European-Finnish (FIN)

AF:

0.283

AC:

2994

AN:

10592

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.297

AC:

20196

AN:

67992

Other (OTH)

AF:

0.303

AC:

640

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1588

3176

4764

6352

7940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.292

Hom.:

11259

Bravo

AF:

0.282

Asia WGS

AF:

0.337

AC:

1171

AN:

3478

EpiCase

AF:

0.297

EpiControl

AF:

0.304

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Glanzmann thrombasthenia

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 17, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.1533A>G (p.Glu511=), no individuals with Glanzmann thrombasthenia were reported with the variant. Moreover, the variant has a minor allele frequency of 0.3455 (6891/19944) in gnomAD, found in the East Asian population, which is considerably higher than the expected frequency of the disease (BA1). In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4 (PD VCEP specifications version 2.1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.3

(source)

DANN

Benign

0.54

PhyloP100

2.1

Mutation Taster

=96/4

polymorphism (auto)

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over