17-44381058-A-G

Position:

• chr17-44381058-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM3_Strong PP4_Strong PP1_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1214T>C (p.Ile405Thr) variant has been reported in at least four compound heterozygous probands (PMIDs: 12424194, 12083483, 24418945, 25728920) with a phenotype highly specific to GT. In one case the variant cosegregated with disease in the proband and two siblings (PMID:12424194). It is absent from Exac and gnomAD. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PM3_Strong, PM2_Supporting, PP1_Moderate, PP3 and PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA290950815/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.06

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 Pathogenic. Variant got 11 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.
• PP1: 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.1214T>C	p.Ile405Thr	missense_variant	13/30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.1367T>C	p.Ile456Thr	missense_variant	13/29		XP_011523051.2
ITGA2B	XM_011524750.2	c.1367T>C	p.Ile456Thr	missense_variant	13/29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1214T>C	p.Ile405Thr	missense_variant	13/30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.644T>C	p.Ile215Thr	missense_variant	9/25			ENSP00000498119.1
ITGA2B	ENST00000592226.5	n.454T>C		non_coding_transcript_exon_variant	7/10	5
ITGA2B	ENST00000592462.5	n.9T>C		non_coding_transcript_exon_variant	2/15	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461000 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726730

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000334 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Mar 05, 2021

The c.1214T>C (p.Ile405Thr) variant has been reported in at least four compound heterozygous probands (PMIDs: 12424194, 12083483, 24418945, 25728920) with a phenotype highly specific to GT. In one case the variant cosegregated with disease in the proband and two siblings (PMID: 12424194). It is absent from Exac and gnomAD. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PM3_Strong, PM2_Supporting, PP1_Moderate, PP3 and PP4_Strong. -

Glanzmann thrombasthenia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.87	P
Vest4		0.88
MutPred		0.95		Loss of stability (P = 0.0166);
MVP		0.91
MPC		0.49
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.73
gMVP		0.81

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: rs75622274; hg19: chr17-42458426;