chr17-47253911-TG-T

Position:

• chr17-47253911-TG-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_Supporting PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.55del variant in ITGB3 is a deletion of 1 nucleotide in exon 1, resulting in a shift of the reading frame and a premature stop signal (p.Ala19Argfs*7). Premature termination codon within exon 1/ first 100 nucleotides may not cause NMD and instead may lead to translation re-initiation (PMID:27618451). Therefore, PVS1 is downgraded to PVS1_moderate. This variant occurs at a very low allele frequency overall in gnomAD v4.0.0 of 0.000006374 with a MAF of 0.000002980 (3/1006570) in the non-Finnish European population (PM2_Supporting). The variant has been reported heterozygous in one individual (PMID:31980526) but has not been reported in any patients with a Glanzmann thrombasthenia phenotype. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA626377544/MONDO:0100326/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: ITGB3 NM_000212.3 frameshift
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• 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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGB3	NM_000212.3	c.55del	p.Ala19ArgfsTer7	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.55del	p.Ala19ArgfsTer7	frameshift_variant	1/15	1	NM_000212.3	ENSP00000452786	P1
ITGB3	ENST00000571680.1	c.55del	p.Ala19ArgfsTer7	frameshift_variant	1/9	1		ENSP00000461626
ITGB3	ENST00000696963.1	c.55del	p.Ala19ArgfsTer7	frameshift_variant	1/14			ENSP00000513002

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000637 AC: 8 AN: 1255010 Hom.: 0 Cov.: 30 AF XY: 0.00000810 AC XY: 5 AN XY: 617396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000414

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000161

Gnomad4 FIN exome AF: 0.0000611

Gnomad4 NFE exome AF: 0.00000298

Gnomad4 OTH exome AF: 0.0000198

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1438062). This variant has not been reported in the literature in individuals affected with ITGB3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ala19Argfs*7) in the ITGB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ITGB3 are known to be pathogenic (PMID: 21917754). -

Glanzmann thrombasthenia Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Feb 20, 2024

The c.55del variant in ITGB3 is a deletion of 1 nucleotide in exon 1, resulting in a shift of the reading frame and a premature stop signal (p.Ala19Argfs*7). Premature termination codon within exon 1/ first 100 nucleotides may not cause NMD and instead may lead to translation re-initiation (PMID: 27618451). Therefore, PVS1 is downgraded to PVS1_moderate. This variant occurs at a very low allele frequency overall in gnomAD v4.0.0 of 0.000006374 with a MAF of 0.000002980 (3/1006570) in the non-Finnish European population (PM2_Supporting). The variant has been reported heterozygous in one individual (PMID: 31980526) but has not been reported in any patients with a Glanzmann thrombasthenia phenotype. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

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: rs1302506624; hg19: chr17-45331277;