17-47284514-G-T

Position:

• chr17-47284514-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3 PM3_Supporting PP1 PP3 PM2_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000212.2(ITGB3):c.433G>T (p.Asp145Tyr) is a missense variant that is expressed normally on the platelet surface, but lacks the function of ligand binding (PMID:2392682, PMID:15583747). It has been reported in 2 siblings with variant GT, in the homozygous state (PMIDs: 2428841, 2392682, 7520434) and a compound heterozygote (with Met150Val;PMID:15583747). It is absent from population databases and has a REVEL score of 0.972 (threshold: >0.7). In summary, based on the available evidence at this time, the variant is classified as Pathogenic. GT-specific criteria applied: PS3, PM2_Supporting, PP1, PP3, PP4_Moderate, PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA123226/MONDO:0010119/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 10.0

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

ENSG00000259753 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.
• 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
ITGB3	NM_000212.3	c.433G>T	p.Asp145Tyr	missense_variant	4/15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7	c.433G>T	p.Asp145Tyr	missense_variant	4/15	1	NM_000212.3	ENSP00000452786.2
ITGB3	ENST00000571680.1	c.433G>T	p.Asp145Tyr	missense_variant	4/9	1		ENSP00000461626.1
ENSG00000259753	ENST00000560629.1	n.397G>T		non_coding_transcript_exon_variant	4/18	2		ENSP00000456711.2
ITGB3	ENST00000696963.1	c.433G>T	p.Asp145Tyr	missense_variant	4/14			ENSP00000513002.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000882 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

Sep 06, 2020

The NM_000212.2(ITGB3):c.433G>T (p.Asp145Tyr) is a missense variant that is expressed normally on the platelet surface, but lacks the function of ligand binding (PMID: 2392682, PMID:15583747). It has been reported in 2 siblings with variant GT, in the homozygous state (PMIDs: 2428841, 2392682, 7520434) and a compound heterozygote (with Met150Val;PMID: 15583747). It is absent from population databases and has a REVEL score of 0.972 (threshold: >0.7). In summary, based on the available evidence at this time, the variant is classified as Pathogenic. GT-specific criteria applied: PS3, PM2_Supporting, PP1, PP3, PP4_Moderate, PM3_Supporting. -

Glanzmann thrombasthenia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 24, 1990

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-8.5	D;.
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.99		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121918445; hg19: chr17-45361880;