rs121918445

Positions:

• chr17-47284514-G-A
• chr17-47284514-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM5 PM3 PP3 PM2_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000212.2:c.433G>A variant that results in the Asp145Asn amino acid change is reported in two homozygous individuals in the literature (PMID:31064749 and Proband NR in PMID:9215749, Blood abstracts 1997 Suppl., & GT database; PM3). An additional homozygous patient has been identified through clinical testing. One published proband (Ward et al., 1997 Blood Abstracts, Vol 90, Suppl. & GT database, MCW), an Arab female (NR) with frequent bruising, gingival bleeding, epistaxis, menorrhagia, requiring >2 platelet transfusions, showed absent platelet aggregation with collagen, arachidonic acid, thrombin, ADP and normal aggregation with ristocetin (PP4_moderate). It is absent in population databases, including gnomADv2.1.1 (PM2_supporting) and is predicted damaging by in-silico tools (REVEL score 0.89; PP3). Asp145Tyr is a variant reported at the same residue and classified as likely pathogenic by the Platelet Disorders VCEP (PM5). In summary, based on the available evidence at this time, the Asp145Asn variant is classified as Likely Pathogenic. GT-specific criteria applied: PM2_supporting, PM3, PP3, PP4_moderate and PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA400021939/MONDO:0010119/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• 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 Likely_pathogenic. Variant got 8 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.
• PM5: 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>A	p.Asp145Asn	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>A	p.Asp145Asn	missense_variant	4/15	1	NM_000212.3	ENSP00000452786.2
ITGB3	ENST00000571680.1	c.433G>A	p.Asp145Asn	missense_variant	4/9	1		ENSP00000461626.1
ENSG00000259753	ENST00000560629.1	n.397G>A		non_coding_transcript_exon_variant	4/18	2		ENSP00000456711.2
ITGB3	ENST00000696963.1	c.433G>A	p.Asp145Asn	missense_variant	4/14			ENSP00000513002.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Nov 02, 2023	The NM_000212.2:c.433G>A variant that results in the Asp145Asn amino acid change is reported in two homozygous individuals in the literature (PMID: 31064749 and Proband NR in PMID: 9215749, Blood abstracts 1997 Suppl., & GT database; PM3). An additional homozygous patient has been identified through clinical testing. One published proband (Ward et al., 1997 Blood Abstracts, Vol 90, Suppl. & GT database, MCW), an Arab female (NR) with frequent bruising, gingival bleeding, epistaxis, menorrhagia, requiring >2 platelet transfusions, showed absent platelet aggregation with collagen, arachidonic acid, thrombin, ADP and normal aggregation with ristocetin (PP4_moderate). It is absent in population databases, including gnomADv2.1.1 (PM2_supporting) and is predicted damaging by in-silico tools (REVEL score 0.89; PP3). Asp145Tyr is a variant reported at the same residue and classified as likely pathogenic by the Platelet Disorders VCEP (PM5). In summary, based on the available evidence at this time, the Asp145Asn variant is classified as Likely Pathogenic. GT-specific criteria applied: PM2_supporting, PM3, PP3, PP4_moderate and PM5. -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

Glanzmann thrombasthenia 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PM3,PP4,PM2,PP3,PM5,PM1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	31
DANN	Pathogenic	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	0.58	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.8	D;.
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.99		Loss of phosphorylation at Y141 (P = 0.1148);Loss of phosphorylation at Y141 (P = 0.1148);
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;