rs121918452

Variant names:

• chr17-47284509-T-C
• rs121918452
• NM_000212.3:c.428T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-47284509-T-C
• chr17-47284509-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM5_Supporting PP4_Moderate PP3 PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000212.3(ITGB3):c.428T>C (p.Leu143Ser) missense variant is absent from gnomADv4.0.0 (PM2_supporting) and has a REVEL score of 0.973, above the >.0.7 threshold in support of a deleterious effect (PP3). Another missense variant NM_000212.3(ITGB3):c.428T>G (p.Leu143Trp) in the same codon has been classified as likely pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP (PM5_supporting). It has been reported once, homozygous in Patient 15 of PMID:36672149 has history of bleeding and impaired aggregation to at least two agonists, but normal agglutination with ristocetin (PM3_supporting; PP4_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PM2_supporting, PP3, PM5_supporting, PM3_supporting, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA400021913/MONDO:0100326/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

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:):

EFCAB13-DT (HGNC:55338): (EFCAB13 divergent transcript)

ACMG classification

Specifications for ITGB3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 6 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000212.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	NM_000212.3	MANE Select	c.428T>C	p.Leu143Ser	missense	Exon 4 of 15	NP_000203.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	ENST00000559488.7	TSL:1 MANE Select	c.428T>C	p.Leu143Ser	missense	Exon 4 of 15	ENSP00000452786.2	P05106-1
	ITGB3	ENST00000571680.1	TSL:1	c.428T>C	p.Leu143Ser	missense	Exon 4 of 9	ENSP00000461626.1	I3L4X8
	ENSG00000259753	ENST00000560629.1	TSL:2	n.392T>C		non_coding_transcript_exon	Exon 4 of 18	ENSP00000456711.2	H3BM21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Glanzmann thrombasthenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		8.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.7	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.91		Loss of catalytic residue at L143 (P = 0.007)
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.96

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

Other links and lift over

dbSNP: rs121918452; hg19: chr17-45361875;