rs121918452

Positions:

• chr17-47284509-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS3 PM3 PP3 PP1 PM2_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The ITGB3 missense variant NM_000212.2:c.428T>G replaces the leucine residue with a tryptophan residue (p.Leu143Trp). This variant has been observed in homozygosity in at least 14 individuals reported to have Glanzmann's thrombasthenia (GT) (PMID:9376589, PMID:26096001, PMID:16463284, PMID:36672149; PM3). PMID:16463284 suggests this variant is a founder variant in Indian populations. At least one patient has a phenotype specific for GT (Patient MK, PMID:9376589) with a history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. Additionally, flow cytometry showed <10% expression of αIIbβ3 (PP4_Moderate). This variant has also been observed to segregate with disease in two affected family members (Patients L and M, PMID:26096001; PP1). Additionally, in silico tools predict the variant is damaging to protein function (REVEL score 0.98; PP3) and transient expression of ITGB3 carrying the variant in 293 cells led to a reduced level of αIIbβ3 and αIIb receptor expression on the cell surface (<5% compared to cells expressing wild type ITGB3, PMID:11806996; PS3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009881 (9/91082 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PS3, PP4_moderate, PP1, PP3, PM2_supporting, PM3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA123252/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.02

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 11 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.428T>G	p.Leu143Trp	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.428T>G	p.Leu143Trp	missense_variant	4/15	1	NM_000212.3	ENSP00000452786.2
ITGB3	ENST00000571680.1	c.428T>G	p.Leu143Trp	missense_variant	4/9	1		ENSP00000461626.1
ENSG00000259753	ENST00000560629.1	n.392T>G		non_coding_transcript_exon_variant	4/18	2		ENSP00000456711.2
ITGB3	ENST00000696963.1	c.428T>G	p.Leu143Trp	missense_variant	4/14			ENSP00000513002.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251478 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135910

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 SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000902 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2024	Variant summary: ITGB3 c.428T>G (p.Leu143Trp) results in a non-conservative amino acid change located in the Integrin beta subunit, VWA domain (IPR002369) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251478 control chromosomes (gnomAD). c.428T>G has been reported in the literature in multiple individuals affected with Glanzmann Thrombasthenia 2 (e.g. Basani_1997, Peretz_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant prevents the export of the protein to the cell surface (Basani_1997). The following publications have been ascertained in the context of this evaluation (PMID: 16463284, 9376589). ClinVar contains an entry for this variant (Variation ID: 13567). Based on the evidence outlined above, the variant was classified as pathogenic. -

Glanzmann thrombasthenia Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Jun 06, 2024

The ITGB3 missense variant NM_000212.2:c.428T>G replaces the leucine residue with a tryptophan residue (p.Leu143Trp). This variant has been observed in homozygosity in at least 14 individuals reported to have Glanzmann's thrombasthenia (GT) (PMID: 9376589, PMID: 26096001, PMID: 16463284, PMID: 36672149; PM3). PMID: 16463284 suggests this variant is a founder variant in Indian populations. At least one patient has a phenotype specific for GT (Patient MK, PMID: 9376589) with a history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin. Additionally, flow cytometry showed <10% expression of αIIbβ3 (PP4_Moderate). This variant has also been observed to segregate with disease in two affected family members (Patients L and M, PMID: 26096001; PP1). Additionally, in silico tools predict the variant is damaging to protein function (REVEL score 0.98; PP3) and transient expression of ITGB3 carrying the variant in 293 cells led to a reduced level of αIIbβ3 and αIIb receptor expression on the cell surface (<5% compared to cells expressing wild type ITGB3, PMID: 11806996; PS3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009881 (9/91082 alleles) in the South Asian population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PS3, PP4_moderate, PP1, PP3, PM2_supporting, PM3. -

Myocardial infarction, susceptibility to;C5543273:Glanzmann thrombasthenia 2;C5543280:Bleeding disorder, platelet-type, 24 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 12, 2024

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ITGB3 function (PMID: 9376589). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ITGB3 protein function. ClinVar contains an entry for this variant (Variation ID: 13567). This variant is also known as Leu117Trp. This missense change has been observed in individuals with Glanzmann thrombasthenia (PMID: 9376589, 16463284, 26096001). This variant is present in population databases (rs121918452, gnomAD 0.02%). This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 143 of the ITGB3 protein (p.Leu143Trp). -

Glanzmann thrombasthenia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Feb 14, 2023

The missense c.428T>G(p.Leu143Trp) variant in ITGB3 gene has been reported in compound heterozygous state in multiple individuals affected with Glanzmann Thrombasthenia (Siddiqi MYJ, et. al., 2023; Peretz H, et. al., 2006). This variant has also been observed to segregate with disease in two affected family members (Haghighi A, et. al., 2016). Evidence of a founder effect was detected in south asian population (Peretz H, et. al., 2006). The variant is reported with an allele frequency of 0.002% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as pathogenic/Likely pathogenic. The amino acid change p.Leu143Trp in ITGB3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 143 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.7	D;.
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.97		Loss of stability (P = 0.0563);Loss of stability (P = 0.0563);
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.92

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: rs121918452; hg19: chr17-45361875;