rs1057518838

Variant names:

• chr17-47286394-A-G
• rs1057518838
• NM_000212.3:c.749A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-47286394-A-G
• chr17-47286394-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3 PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.749A>G variant in ITGB3 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 250. The variant has been reported in at least one patient (Glanzmann Patient, "HEMOSTAZA SKOZIKLINIČNE PRIMERE" August 2022) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). This individual is compound heterozygous for this variant and pathogenic variant c.1699C>T (p.Gln567Ter) (PM3). The variant is absent from gnomAD (PM2_supporting). The computational predictor REVEL gives a score of 0.988, which is above the ClinGen PD VCEP PP3 threshold of >0.7 and predicts a damaging effect on ITGB3 function. In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PP3, PP4_moderate, and PM3. (VCEP specifications version 2) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16043530/MONDO:0100326/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB3 ENST00000559488.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.32
• 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

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.
• 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: ENST00000559488.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	NM_000212.3	MANE Select	c.749A>G	p.Asp250Gly	missense	Exon 5 of 15	NP_000203.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	ENST00000559488.7	TSL:1 MANE Select	c.749A>G	p.Asp250Gly	missense	Exon 5 of 15	ENSP00000452786.2
	ITGB3	ENST00000571680.1	TSL:1	c.749A>G	p.Asp250Gly	missense	Exon 5 of 9	ENSP00000461626.1
	ENSG00000259753	ENST00000560629.1	TSL:2	n.713A>G		non_coding_transcript_exon	Exon 5 of 18	ENSP00000456711.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Glanzmann thrombasthenia (1)
1	-	-	Platelet-type bleeding disorder 16 (1)
1	-	-	Prolonged bleeding time;C1458140:Abnormal bleeding (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.8	D
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.94		Gain of catalytic residue at D250 (P = 0.0195)
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
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: rs1057518838; hg19: chr17-45363760;