chr17-44372422-A-G

Position:

• chr17-44372422-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PP4_Strong PM2_Supporting BP4 PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.3062T>C (p.Val1021Ala) missense variant has been reported in at least two Glanzmann thrombasthenia patients (PMID:21113249). Patient SB displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 23%, as measured by flow cytometry, and there was 12-13% binding to PAC-1. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong; PMID:21113249). Patient LN is homozygous for c.3062T>C (PM3_supporting; PMID:21113249). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.084, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2 function (BP4). 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: PP4_strong, PM2_supporting, PM3_supporting, and BP4. (VCEP specifications version 2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA399787956/MONDO:0100326/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGA2B NM_000419.5 missense, splice_region
• Scores: Splicing: ADA: 0.003034
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: -0.556

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 Uncertain_significance. Variant got 5 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.3062T>C	p.Val1021Ala	missense_variant, splice_region_variant	30/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.3113T>C	p.Val1038Ala	missense_variant, splice_region_variant	29/29
ITGA2B	XM_011524750.2	c.3098T>C	p.Val1033Ala	missense_variant, splice_region_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3062T>C	p.Val1021Ala	missense_variant, splice_region_variant	30/30	1	NM_000419.5	P1
ITGA2B	ENST00000648408.1	c.2378T>C	p.Val793Ala	missense_variant, splice_region_variant	25/25
ITGA2B	ENST00000587295.5	c.257T>C	p.Val86Ala	missense_variant, splice_region_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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 02, 2021

The NM_000419.5(ITGA2B):c.3062T>C (p.Val1021Ala) missense variant has been reported in at least two Glanzmann thrombasthenia patients (PMID: 21113249). Patient SB displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 23%, as measured by flow cytometry, and there was 12-13% binding to PAC-1. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong; PMID: 21113249). Patient LN is homozygous for c.3062T>C (PM3_supporting; PMID: 21113249). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.084, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2 function (BP4). 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: PP4_strong, PM2_supporting, PM3_supporting, and BP4. (VCEP specifications version 2; date of approval 09/02/2021). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	2.0
DANN	Benign	0.81
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.68	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.084
Sift	Benign	0.34	T
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.021
MutPred		0.46		Loss of stability (P = 0.0832);
MVP		0.48
MPC		0.35
ClinPred		0.031	T
GERP RS		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42449790;