chr17-44380626-G-A

Position:

• chr17-44380626-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP7 BP4

This summary comes from the ClinGen Evidence Repository: After a comprehensive literature search of the synonymous variant NM_000419.5(ITGA2B):c.1413C>T (p.Tyr471=), no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.0005513 (11/19954 alleles) based off the East Asian population, which does not meet threshold for PM2_supporting or BS1. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -1.38 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 and BP7 (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8603102/MONDO:0100326/011

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ITGA2B NM_000419.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:2
• Conservation: PhyloP100: -1.68

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.1413C>T	p.Tyr471=	synonymous_variant	14/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.1566C>T	p.Tyr522=	synonymous_variant	14/29
ITGA2B	XM_011524750.2	c.1566C>T	p.Tyr522=	synonymous_variant	14/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1413C>T	p.Tyr471=	synonymous_variant	14/30	1	NM_000419.5	P1
ITGA2B	ENST00000648408.1	c.846C>T	p.Tyr282=	synonymous_variant	10/25
ITGA2B	ENST00000592226.5	n.886C>T		non_coding_transcript_exon_variant	7/10	5
ITGA2B	ENST00000592462.5	n.208C>T		non_coding_transcript_exon_variant	3/15	5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152162 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: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251476 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

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: 0.0000233 AC: 34 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000415 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Benign:2

Likely benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Aug 15, 2023	After a comprehensive literature search of the synonymous variant NM_000419.5(ITGA2B):c.1413C>T (p.Tyr471=), no individuals with Glanzmann Thrombasthenia were reported with the variant. The variant has a high minor allele frequency of 0.0005513 (11/19954 alleles) based off the East Asian population, which does not meet threshold for PM2_supporting or BS1. In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of -1.38 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4 and BP7 (PD VCEP specifications version 2.1). -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.41
DANN	Benign	0.22
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

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: rs78218617; hg19: chr17-42457994; COSMIC: COSV52235307; COSMIC: COSV52235307;