17-47283340-C-A

Position:

• chr17-47283340-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM3_Supporting BP7 PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The ITGB3 intronic variant NM_000212.3:c.166-14C>A is not predicted by in silico tools to have an impact on splicing and is not highly conserved (BP7). This variant has been observed in homozygosity (PM3_supporting) in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT03, PMID:16463284). All requirements for PP4_Moderate are met (GT03 in PMID:16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. This variant is rare in population databases (1/91018 alleles in the South Asian population in gnomAD v4.1.0; PM2_Supporting). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PP4_Moderate, PM2_Supporting, PM3_Supporting, and BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8622881/MONDO:0100326/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITGB3 NM_000212.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:1
• Conservation: PhyloP100: -0.482

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.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.166-14C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7	c.166-14C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000212.3	ENSP00000452786	P1
ITGB3	ENST00000571680.1	c.166-14C>A		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000461626
ITGB3	ENST00000696963.1	c.166-14C>A		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000513002

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250558 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135430

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461574 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727060

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Aug 20, 2024

The ITGB3 intronic variant NM_000212.3:c.166-14C>A is not predicted by in silico tools to have an impact on splicing and is not highly conserved (BP7). This variant has been observed in homozygosity (PM3_supporting) in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT03, PMID: 16463284). All requirements for PP4_Moderate are met (GT03 in PMID: 16463284): history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. This variant is rare in population databases (1/91018 alleles in the South Asian population in gnomAD v4.1.0; PM2_Supporting). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PP4_Moderate, PM2_Supporting, PM3_Supporting, and BP7. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.5
DANN	Benign	0.51

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: rs749373796; hg19: chr17-45360706;