rs3809863

Variant names:

• chr17-47307646-C-T
• rs3809863
• NM_000212.3:c.2301+9C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BA1 BP4

This summary comes from the ClinGen Evidence Repository: After a comprehensive literature search of the intronic variant NM_000212.3(ITGB3):c.2301+9C>T, no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.4805 (11916/24800 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets BA1. In silico predictor spliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of -.336 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 and BP7 (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8623491/MONDO:0100326/011

• Frequency:
  • Genomes: 𝑓 0.46 (16187 hom., cov: 32)
  • Exomes 𝑓: 0.46 (158722 hom.)
• Consequence: ITGB3 NM_000212.3 intron
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.370
• Publications: 38 publications found

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:):

EFCAB13-DT (HGNC:55338): (EFCAB13 divergent transcript)

ACMG classification

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	c.2301+9C>T		intron_variant	Intron 14 of 14	ENST00000559488.7	NP_000203.2
EFCAB13-DT	NR_110880.1	n.363-3864G>A		intron_variant	Intron 2 of 2
EFCAB13-DT	NR_110881.1	n.227-3864G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7	c.2301+9C>T		intron_variant	Intron 14 of 14	1	NM_000212.3	ENSP00000452786.2
ENSG00000259753	ENST00000560629.1	n.2265+9C>T		intron_variant	Intron 14 of 17	2		ENSP00000456711.2

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69311 AN: 151934 Hom.: 16185 Cov.: 32

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.439

GnomAD2 exomes AF: 0.429 AC: 107220 AN: 249968 AF XY: 0.431

Gnomad AFR exome AF: 0.482

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.419

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.463 AC: 676003 AN: 1460176 Hom.: 158722 Cov.: 36 AF XY: 0.461 AC XY: 335190 AN XY: 726390

African (AFR) AF: 0.475 AC: 15897 AN: 33440

American (AMR) AF: 0.356 AC: 15872 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 10915 AN: 26120

East Asian (EAS) AF: 0.269 AC: 10683 AN: 39674

South Asian (SAS) AF: 0.389 AC: 33552 AN: 86166

European-Finnish (FIN) AF: 0.493 AC: 26318 AN: 53374

Middle Eastern (MID) AF: 0.388 AC: 2239 AN: 5766

European-Non Finnish (NFE) AF: 0.480 AC: 533193 AN: 1110700

Other (OTH) AF: 0.453 AC: 27334 AN: 60354

GnomAD4 genome AF: 0.456 AC: 69347 AN: 152052 Hom.: 16187 Cov.: 32 AF XY: 0.453 AC XY: 33674 AN XY: 74310

African (AFR) AF: 0.480 AC: 19888 AN: 41456

American (AMR) AF: 0.374 AC: 5714 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1501 AN: 3470

East Asian (EAS) AF: 0.252 AC: 1305 AN: 5180

South Asian (SAS) AF: 0.381 AC: 1835 AN: 4810

European-Finnish (FIN) AF: 0.499 AC: 5277 AN: 10572

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.476 AC: 32356 AN: 67974

Other (OTH) AF: 0.438 AC: 924 AN: 2108

Alfa AF: 0.463 Hom.: 57034

Bravo AF: 0.449

Asia WGS AF: 0.295 AC: 1027 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Apr 06, 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 intronic variant NM_000212.3(ITGB3):c.2301+9C>T, no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.4805 (11916/24800 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets BA1. In silico predictor spliceAI revealed that the intronic mutation is not expected to impact splicing and a PhyloP score of -.336 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 and BP7 (PD VCEP specifications version 2.1). -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.87
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3809863; hg19: chr17-45385012; COSMIC: COSV107525062; COSMIC: COSV107525062;