rs76811038

Variant names:

• chr17-44379780-A-G
• rs76811038
• NM_000419.5:c.1787T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-44379780-A-G
• chr17-44379780-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4_Strong PP1 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.1787T>C (p.Ile596Thr) missense variant has been reported in the homozygous state in at least 2 apparently unrelated individuals (PMID:22513797, 20020534) and in the compound heterozygous state in 4 individuals (PMID:9215749, 9734640, 34552732, 25373348). The second variants in these patients are c.3060+2T>C (classified Pathogenic by the PD-VCEP; without confirmation of trans phase), Glu355Lys (classified Pathogenic by the PD-VCEP; with confirmation of trans phase), c.2841+1G>T, and c.408G>C (latter two not considered here to avoid circularity) respectively (PM3_Strong). The proband from PMID:22513797 meets criteria for PP4_Strong including mucocutaneous bleeding; abnormal platelet aggregometry in response to at least 2 agonist and normal response to ristocetin; absent surface expression of GPIIb-IIIa on flow cytometry; and full sequencing of ITGA2B and ITGB3. It was found to co-segregate with disease in 1 additional family member (PP1). Ile596Thr is reported in gnomAD v4.0.0 at a frequency of 0.00008305 (98/1179968 alleles) in the non-Finnish European population, below the PM2_supporting threshold of <0.0001. In summary, this variant is classified Pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific codes applied: PP4_Strong, PM2_Supporting, PM3_Strong, PP1. (PD-VCEP specifications version 2) LINK:https://erepo.genome.network/evrepo/ui/classification/CA115846/MONDO:0100326/011

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 6.13
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 16

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Glanzmann thrombasthenia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann's thrombasthenia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Glanzmann thrombasthenia 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000419.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	NM_000419.5	MANE Select	c.1787T>C	p.Ile596Thr	missense	Exon 18 of 30	NP_000410.2	P08514-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.1787T>C	p.Ile596Thr	missense	Exon 18 of 30	ENSP00000262407.5	P08514-1
	ITGA2B	ENST00000901307.1		c.1787T>C	p.Ile596Thr	missense	Exon 18 of 29	ENSP00000571366.1
	ITGA2B	ENST00000949677.1		c.1787T>C	p.Ile596Thr	missense	Exon 18 of 29	ENSP00000619736.1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

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: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000638 AC: 16 AN: 250706 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000657 AC: 96 AN: 1461712 Hom.: 0 Cov.: 33 AF XY: 0.0000605 AC XY: 44 AN XY: 727160

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000827 AC: 92 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151884 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74182

African (AFR) AF: 0.0000484 AC: 2 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000792 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Glanzmann thrombasthenia (2)
2	-	-	Glanzmann thrombasthenia 1 (2)
1	-	-	ITGA2B-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.069	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.95		Loss of stability (P = 0.0055)
MVP		0.87
MPC		1.1
ClinPred		0.57	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.87
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs76811038; hg19: chr17-42457148;