NM_000212.3:c.433G>A

Variant names:

• chr17-47284514-G-A
• rs121918445
• NM_000212.3:c.433G>A

Variant summary

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

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 rank	MANE	Protein	UniProt
ITGB3	NM_000212.3	c.433G>A	p.Asp145Asn	missense_variant	Exon 4 of 15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7	c.433G>A	p.Asp145Asn	missense_variant	Exon 4 of 15	1	NM_000212.3	ENSP00000452786.2
ITGB3	ENST00000571680.1	c.433G>A	p.Asp145Asn	missense_variant	Exon 4 of 9	1		ENSP00000461626.1
ENSG00000259753	ENST00000560629.1	n.397G>A		non_coding_transcript_exon_variant	Exon 4 of 18	2		ENSP00000456711.2
ITGB3	ENST00000696963.1	c.433G>A	p.Asp145Asn	missense_variant	Exon 4 of 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

Nov 02, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Glanzmann thrombasthenia 2 Pathogenic:1

Oct 04, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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;