chr17-44376323-T-G

Variant names:

• chr17-44376323-T-G
• rs74475415
• NM_000419.5:c.2333A>C

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PP4_Strong PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000419.4:c.2333A>C variant that results in the p.Gln778Pro amino acid change is reported in at least 5 homozygous and 6 compound heterozygous probands in the literature (PMID:9722314, 22190468, 9763559, 29675921, 32237906). At least 5 variants in trans with Gln778Pro have been curated and evaluated for PM3 scoring. The variant is reported at frequency <0.0001 in the combined gnomAD v3 and v2.1.1 datasets. In summary, based on the available evidence at this time, the Gln778Pro variant is classified as pathogenic. GT-specific criteria applied: PM2_Supporting, PM3_Strong, PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA290947544/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: -0.170
• Publications: 9 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 9 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.
• 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.2333A>C	p.Gln778Pro	missense	Exon 23 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.2333A>C	p.Gln778Pro	missense	Exon 23 of 30	ENSP00000262407.5	P08514-1
	ITGA2B	ENST00000901307.1		c.2333A>C	p.Gln778Pro	missense	Exon 23 of 29	ENSP00000571366.1
	ITGA2B	ENST00000949677.1		c.2333A>C	p.Gln778Pro	missense	Exon 23 of 29	ENSP00000619736.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251464 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 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: 0.000327 AC: 13 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	-	-	Platelet-type bleeding disorder 16;CN300358:Glanzmann thrombasthenia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.17
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.27
Sift	Benign	0.15	T
Sift4G	Benign	0.19	T
Polyphen		0.38	B
Vest4		0.45
MutPred		0.87		Loss of sheet (P = 0.0817)
MVP		0.70
MPC		0.56
ClinPred		0.14	T
GERP RS		-3.0
PromoterAI		-0.22	Neutral
Varity_R		0.52
gMVP		0.84
Mutation Taster		=36/64	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs74475415; hg19: chr17-42453691;