chr17-44375719-G-T

Position:

• chr17-44375719-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP4_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.4:c.2602-3C>A is a splice region variant in intron 25. The variant occurs at a very low frequency in population databases, with 0.00003830 (1/26801 alleles) in the gnomADv2.1.1 Latino/Admixed American population (PM2_supporting). It is reported in one compound heterozygous individual with the c.2602-2A>G and Thr281Ile (PMID:25373348). GT16 of PMID:25373348 meets bleeding phenotype, aggregometry criteria, integrin expression is reported to be <5% reduced by flow cytometry, and all exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were sequenced (PP4_strong). In summary, there is insufficient evidence at this time to classify this variant for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PM2_Supporting, PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8602635/MONDO:0010119/011

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ITGA2B NM_000419.5 splice_region, intron
• Scores: Splicing: ADA: 0.7670
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 0.978

Genes affected

ITGA2B (HGNC:6138): (integrin subunit alpha 2b) This gene encodes a member of the integrin alpha chain family of proteins. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate through disulfide linkages to form a subunit of the alpha-IIb/beta-3 integrin cell adhesion receptor. This receptor plays a crucial role in the blood coagulation system, by mediating platelet aggregation. Mutations in this gene are associated with platelet-type bleeding disorders, which are characterized by a failure of platelet aggregation, including Glanzmann thrombasthenia. [provided by RefSeq, Jan 2016]

ITGA2B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.2602-3C>A		splice_region_variant, intron_variant		ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.2755-3C>A		splice_region_variant, intron_variant			XP_011523051.2
ITGA2B	XM_011524750.2	c.2755-3C>A		splice_region_variant, intron_variant			XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.2602-3C>A		splice_region_variant, intron_variant		1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.2032-3C>A		splice_region_variant, intron_variant				ENSP00000498119.1
ITGA2B	ENST00000587295.5	c.252+114C>A		intron_variant		3		ENSP00000467269.1
ITGA2B	ENST00000592462.5	n.1397-3C>A		splice_region_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181340 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 97246

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000383

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1420694 Hom.: 0 Cov.: 34 AF XY: 0.00000284 AC XY: 2 AN XY: 703150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000367

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain: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

Sep 07, 2023

The NM_000419.4:c.2602-3C>A is a splice region variant in intron 25. The variant occurs at a very low frequency in population databases, with 0.00003830 (1/26801 alleles) in the gnomADv2.1.1 Latino/Admixed American population (PM2_supporting). It is reported in one compound heterozygous individual with the c.2602-2A>G and Thr281Ile (PMID: 25373348). GT16 of PMID: 25373348 meets bleeding phenotype, aggregometry criteria, integrin expression is reported to be <5% reduced by flow cytometry, and all exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were sequenced (PP4_strong). In summary, there is insufficient evidence at this time to classify this variant for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PM2_Supporting, PP4_Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.59
SpliceAI score (max)		0.070		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: rs763330792; hg19: chr17-42453087;