17-47292411-A-G

Position:

chr17-47292411-A-G

Variant summary

Our verdict is Benign. Variant got -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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ITGB3	NM_000212.3 link	c.1533A>G	p.Glu511Glu	synonymous_variant	10/15	ENST00000559488.7	NP_000203.2	P05106-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ITGB3	ENST00000559488.7 link	c.1533A>G	p.Glu511Glu	synonymous_variant	10/15	1	NM_000212.3	ENSP00000452786.2	P05106-1
ENSG00000259753	ENST00000560629.1 link	n.1497A>G		non_coding_transcript_exon_variant	10/18	2		ENSP00000456711.2	H3BM21
ITGB3	ENST00000696963.1 link	c.1533A>G	p.Glu511Glu	synonymous_variant	10/14			ENSP00000513002.1	P05106-2

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

GnomAD3 exomes

AF:

0.286

AC:

71739

AN:

250598

Hom.:

10357

AF XY:

0.289

AC XY:

39107

AN XY:

135462

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 SAS exome

AF:

0.292

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

Gnomad4 AFR exome

AF:

0.274

Gnomad4 AMR exome

AF:

0.235

Gnomad4 ASJ exome

AF:

0.288

Gnomad4 EAS exome

AF:

0.341

Gnomad4 SAS exome

AF:

0.294

Gnomad4 FIN exome

AF:

0.291

Gnomad4 NFE exome

AF:

0.290

Gnomad4 OTH exome

AF:

0.293

GnomAD4 genome

AF:

0.286

AC:

43560

AN:

152154

Hom.:

6393

Cov.:

AF XY:

0.285

AC XY:

21232

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.265

Gnomad4 AMR

AF:

0.280

Gnomad4 ASJ

AF:

0.282

Gnomad4 EAS

AF:

0.333

Gnomad4 SAS

AF:

0.294

Gnomad4 FIN

AF:

0.283

Gnomad4 NFE

AF:

0.297

Gnomad4 OTH

AF:

0.303

Alfa

AF:

0.291

Hom.:

3597

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glanzmann thrombasthenia

Benign:2

Benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Oct 17, 2023	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). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.3

DANN

Benign

0.54

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over