rs4634

Variant names:

• chr17-47292423-G-A
• rs4634
• NM_000212.3:c.1545G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7 BA1 BP4

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
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.237

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]

ENSG00000259753 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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	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	c.1545G>A	p.Arg515Arg	synonymous_variant	Exon 10 of 15	1	NM_000212.3	ENSP00000452786.2
ENSG00000259753	ENST00000560629.1	n.1509G>A		non_coding_transcript_exon_variant	Exon 10 of 18	2		ENSP00000456711.2
ITGB3	ENST00000696963.1	c.1545G>A	p.Arg515Arg	synonymous_variant	Exon 10 of 14			ENSP00000513002.1

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43520 AN: 152040 Hom.: 6378 Cov.: 33

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: 71672 AN: 250356 Hom.: 10352 AF XY: 0.289 AC XY: 39068 AN XY: 135296

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 SAS exome AF: 0.293

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.: 38 AF XY: 0.289 AC XY: 209879 AN XY: 725170

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: 43552 AN: 152158 Hom.: 6387 Cov.: 33 AF XY: 0.285 AC XY: 21226 AN XY: 74366

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: 0.290 Hom.: 3354

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

Submissions by phenotype

not specified Benign:3

-

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

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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 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). -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.6
DANN	Benign	0.49

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

Other links and lift over

dbSNP: rs4634; hg19: chr17-45369789; COSMIC: COSV71383299; COSMIC: COSV71383299;