17-47283379-G-A

Position:

• chr17-47283379-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The ITGB3 missense variant NM_000212.3:c.191G>A replaces the cysteine residue with a tyrosine residue (p.Cys64Tyr). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-21 in PMID:20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and a second ITGB3 variant was not identified. The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-15% compared to wild type; PMID:20020534; PS3_supporting). The variant is also absent from control population databases including gnomADv4.1.0 (PM2_supporting) and predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.981; PP3). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA291224490/MONDO:0100326/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB3 ENST00000559488.7 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.
• PP3: 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.191G>A	p.Cys64Tyr	missense_variant	3/15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7	c.191G>A	p.Cys64Tyr	missense_variant	3/15	1	NM_000212.3	ENSP00000452786	P1
ITGB3	ENST00000571680.1	c.191G>A	p.Cys64Tyr	missense_variant	3/9	1		ENSP00000461626
ITGB3	ENST00000696963.1	c.191G>A	p.Cys64Tyr	missense_variant	3/14			ENSP00000513002

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Aug 20, 2024

The ITGB3 missense variant NM_000212.3:c.191G>A replaces the cysteine residue with a tyrosine residue (p.Cys64Tyr). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-21 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and a second ITGB3 variant was not identified. The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-15% compared to wild type; PMID: 20020534; PS3_supporting). The variant is also absent from control population databases including gnomADv4.1.0 (PM2_supporting) and predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.981; PP3). In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
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	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-10	D;.
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.98		Loss of disorder (P = 0.0736);Loss of disorder (P = 0.0736);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs74554539; hg19: chr17-45360745;