rs4634

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7BA1BP4

This summary comes from the ClinGen Evidence Repository: After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.1545G>A (p.Arg515=), no individuals with Glanzmann thrombasthenia were reported with the variant. Moreover, the variant has a minor allele frequency of 0.3455 (6891/19946 alleles) 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 and a PhyloP score of 0.285 shows that the nucleotide position is not highly conserved (BP4, BP7). 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, BP7 (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8623284/MONDO:0100326/011

Frequency

Genomes: 𝑓 0.29 ( 6387 hom., cov: 33)

Exomes 𝑓: 0.29 ( 61521 hom. )

Consequence

ITGB3
NM_000212.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 0.237

Publications

29 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 -10 ACMG points.

BP4

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

BP7

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.1545G>A	p.Arg515Arg	synonymous_variant	Exon 10 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.1545G>A	p.Arg515Arg	synonymous_variant	Exon 10 of 15	1	NM_000212.3	ENSP00000452786.2
ENSG00000259753	ENST00000560629.1 link	n.1509G>A		non_coding_transcript_exon_variant	Exon 10 of 18	2		ENSP00000456711.2

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43520

AN:

152040

Hom.:

6378

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:

71672

AN:

250356

AF XY:

0.289

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.230

Gnomad ASJ exome

AF:

0.291

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:

422143

AN:

1458868

Hom.:

61521

Cov.:

AF XY:

0.289

AC XY:

209879

AN XY:

725170

show subpopulations

African (AFR)

AF:

0.274

AC:

9152

AN:

33440

American (AMR)

AF:

0.235

AC:

10506

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

7510

AN:

26050

East Asian (EAS)

AF:

0.341

AC:

13532

AN:

39630

South Asian (SAS)

AF:

0.294

AC:

25340

AN:

86190

European-Finnish (FIN)

AF:

0.291

AC:

15486

AN:

53248

Middle Eastern (MID)

AF:

0.300

AC:

1726

AN:

5752

European-Non Finnish (NFE)

AF:

0.290

AC:

321260

AN:

1109612

Other (OTH)

AF:

0.293

AC:

17631

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

17997

35995

53992

71990

89987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10620

21240

31860

42480

53100

<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:

43552

AN:

152158

Hom.:

6387

Cov.:

AF XY:

0.285

AC XY:

21226

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.265

AC:

11020

AN:

41520

American (AMR)

AF:

0.280

AC:

4277

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

979

AN:

3472

East Asian (EAS)

AF:

0.333

AC:

1720

AN:

5166

South Asian (SAS)

AF:

0.294

AC:

1417

AN:

4824

European-Finnish (FIN)

AF:

0.283

AC:

2991

AN:

10586

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.297

AC:

20181

AN:

67988

Other (OTH)

AF:

0.303

AC:

639

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1552

3104

4656

6208

7760

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:

0.288

Hom.:

3871

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glanzmann thrombasthenia

Benign:2

Jan 12, 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. -

Jan 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.1545G>A (p.Arg515=), no individuals with Glanzmann thrombasthenia were reported with the variant. Moreover, the variant has a minor allele frequency of 0.3455 (6891/19946 alleles) 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 and a PhyloP score of 0.285 shows that the nucleotide position is not highly conserved (BP4, BP7). 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, BP7 (PD VCEP specifications version 2.1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.6

(source)

DANN

Benign

0.49

PhyloP100

0.24

Mutation Taster

=100/0

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