rs80277041

Positions:

• chr17-44379689-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_Strong PM3 PM4 PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1878G>C; p.Gln626His splicing variant has been reported in at least 5 GT probands (PMIDs: 20020534, 22513797, 25728920, 21113249, 29474205) and co-segregated in one additional affected family member (PMID:22513797). It is absent from ExAC and gnomAD. Flow cytometric studies of the mutant protein expressed in COS-7 cells showed that the mutation did not prevent expression of the GPIIb/IIIa complex on the cell surface (PMID:20020534). However, the mutation was found to result in a splice site error, skipping of exon 18, which could explain the absence of mRNA in the patients (PMID:20020534). Splicing predictors, HSF and MaxEntScan, agree that there is alteration to the WT donor site, most likely affecting splicing. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM4, PP3, PP4_Strong, and PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115852/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITGA2B ENST00000262407.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 2.06

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]

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.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1878G>C	p.Gln626His	missense_variant, splice_region_variant	18/30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.2031G>C	p.Gln677His	missense_variant, splice_region_variant	18/29		XP_011523051.2
ITGA2B	XM_011524750.2	c.2031G>C	p.Gln677His	missense_variant, splice_region_variant	18/29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.1878G>C	p.Gln626His	missense_variant, splice_region_variant	18/30	1	NM_000419.5	ENSP00000262407	P1
ITGA2B	ENST00000648408.1	c.1311G>C	p.Gln437His	missense_variant, splice_region_variant	14/25			ENSP00000498119
ITGA2B	ENST00000592462.5	n.673G>C		splice_region_variant, non_coding_transcript_exon_variant	7/15	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461638 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Sep 04, 2020

The c.1878G>C; p.Gln626His splicing variant has been reported in at least 5 GT probands (PMIDs: 20020534, 22513797, 25728920, 21113249, 29474205) and co-segregated in one additional affected family member (PMID: 22513797). It is absent from ExAC and gnomAD. Flow cytometric studies of the mutant protein expressed in COS-7 cells showed that the mutation did not prevent expression of the GPIIb/IIIa complex on the cell surface (PMID: 20020534). However, the mutation was found to result in a splice site error, skipping of exon 18, which could explain the absence of mRNA in the patients (PMID: 20020534). Splicing predictors, HSF and MaxEntScan, agree that there is alteration to the WT donor site, most likely affecting splicing. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM4, PP3, PP4_Strong, and PP1. -

Glanzmann thrombasthenia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.78		Loss of sheet (P = 0.1398);
MVP		0.84
MPC		0.96
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.84
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs80277041; hg19: chr17-42457057;