chr17-47253911-T-TG

Position:

• chr17-47253911-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_Supporting PM3_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: NM_000212.3(ITGB3):c.55dup (p.Ala19GlyfsTer?) is a frameshift variant in exon 1 predicted to cause a premature stop codon in biologically-relevant-exon 2/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Patient TGP0454, PMID:31064749, is reported to have a clinical diagnosis of GT type 1 and is homozygous for this variant (PM3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting (VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA915940803/MONDO:0100326/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: ITGB3 NM_000212.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 3.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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	c.55dup	p.Ala19GlyfsTer36	frameshift_variant	1/15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7	c.55dup	p.Ala19GlyfsTer36	frameshift_variant	1/15	1	NM_000212.3	ENSP00000452786	P1
ITGB3	ENST00000571680.1	c.55dup	p.Ala19GlyfsTer36	frameshift_variant	1/9	1		ENSP00000461626
ITGB3	ENST00000696963.1	c.55dup	p.Ala19GlyfsTer36	frameshift_variant	1/14			ENSP00000513002

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.97e-7 AC: 1 AN: 1255038 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 617406

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000306

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Mar 21, 2023	NM_000212.3(ITGB3):c.55dup (p.Ala19GlyfsTer?) is a frameshift variant in exon 1 predicted to cause a premature stop codon in biologically-relevant-exon 2/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Patient TGP0454, PMID:31064749, is reported to have a clinical diagnosis of GT type 1 and is homozygous for this variant (PM3_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PM2_supporting, PM3_supporting (VCEP specifications version 2.1). -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1302506624; hg19: chr17-45331277;