3-129061811-T-G

Variant names:

• chr3-129061811-T-G
• NM_000174.5:c.72T>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM5_Supporting PP1 PP4 PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000174.5(GP9):c.72T>G (p.Cys24Trp) missense variant is absent from gnomAD v4.1 (PM2_Supporting). Another missense variant in the same codon has been reported in a patient with Bernard-Soulier syndrome [c.70T>C (p.Cys24Arg)] (PMID:21173099) and classified Likely Pathogenic by the PD-VCEP (PM5_supporting). At least one patient (Patient P7 in PMID:21173099) with this variant had less than 10% expression of GPIba and GP9 measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. This individual was homozygous for the variant (PM3_supporting) and one affected first degree relative was also homozygous (PP1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM5_supporting, PP4, PM3_supporting, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA354446617/MONDO:0009276/083

• Frequency: Genomes: not found (cov: 33)
• Consequence: GP9 NM_000174.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: -0.887

Genes affected

GP9 (HGNC:4444): (glycoprotein IX platelet) This gene encodes a small membrane glycoprotein found on the surface of human platelets. It forms a 1-to-1 noncovalent complex with glycoprotein Ib, a platelet surface membrane glycoprotein complex that functions as a receptor for von Willebrand factor. The complete receptor complex includes noncovalent association of the alpha and beta subunits with the protein encoded by this gene and platelet glycoprotein V. Defects in this gene are a cause of Bernard-Soulier syndrome, also known as giant platelet disease. These patients have unusually large platelets and have a clinical bleeding tendency. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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.
• PP1: 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
GP9	NM_000174.5	c.72T>G	p.Cys24Trp	missense_variant	Exon 3 of 3	ENST00000307395.5	NP_000165.1
GP9	XM_047447997.1	c.72T>G	p.Cys24Trp	missense_variant	Exon 2 of 2		XP_047303953.1
GP9	XM_005247374.4	c.*274T>G		downstream_gene_variant			XP_005247431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5	c.72T>G	p.Cys24Trp	missense_variant	Exon 3 of 3	1	NM_000174.5	ENSP00000303942.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Bernard Soulier syndrome Uncertain:1

Feb 11, 2025

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000174.5(GP9):c.72T>G (p.Cys24Trp) missense variant is absent from gnomAD v4.1 (PM2_Supporting). Another missense variant in the same codon has been reported in a patient with Bernard-Soulier syndrome [c.70T>C (p.Cys24Arg)] (PMID:21173099) and classified Likely Pathogenic by the PD-VCEP (PM5_supporting). At least one patient (Patient P7 in PMID:21173099) with this variant had less than 10% expression of GPIba and GP9 measured by flow cytometry, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. This individual was homozygous for the variant (PM3_supporting) and one affected first degree relative was also homozygous (PP1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM5_supporting, PP4, PM3_supporting, PP1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-9.4	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.79		Loss of catalytic residue at P23 (P = 0.005);
MVP		0.94
MPC		0.81
ClinPred		0.99	D
GERP RS		-0.13
Varity_R		0.91
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-128780654;