chr17-44381058-A-G

Variant names:

• chr17-44381058-A-G
• rs75622274
• NM_000419.5:c.1214T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP1_Moderate PP4_Strong PM2_Supporting PM3_Strong

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
• Publications: 6 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Glanzmann thrombasthenia

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• 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 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	NM_000419.5	MANE Select	c.1214T>C	p.Ile405Thr	missense	Exon 13 of 30	NP_000410.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.1214T>C	p.Ile405Thr	missense	Exon 13 of 30	ENSP00000262407.5
	ITGA2B	ENST00000901307.1		c.1214T>C	p.Ile405Thr	missense	Exon 13 of 29	ENSP00000571366.1
	ITGA2B	ENST00000949677.1		c.1214T>C	p.Ile405Thr	missense	Exon 13 of 29	ENSP00000619736.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111648

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000334 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Glanzmann thrombasthenia (1)
1	-	-	Glanzmann thrombasthenia 1 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.1
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
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs75622274; hg19: chr17-42458426;