3-129061741-T-C

Variant names:

• chr3-129061741-T-C
• NM_000174.5:c.2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000174.5(GP9):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GP9 NM_000174.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.367

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 32 codons. Genomic position: 129061833. Lost 0.176 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-129061741-T-C is Pathogenic according to our data. Variant chr3-129061741-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2190152.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP9	NM_000174.5	c.2T>C	p.Met1?	start_lost	Exon 3 of 3	ENST00000307395.5	NP_000165.1
GP9	XM_047447997.1	c.2T>C	p.Met1?	start_lost	Exon 2 of 2		XP_047303953.1
GP9	XM_005247374.4	c.*204T>C		downstream_gene_variant			XP_005247431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5	c.2T>C	p.Met1?	start_lost	Exon 3 of 3	1	NM_000174.5	ENSP00000303942.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GP9 protein in which other variant(s) (p.Cys24Arg) have been determined to be pathogenic (PMID: 11167791, 21173099, 21699652, 23402648). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with GP9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GP9 mRNA. The next in-frame methionine is located at codon 32. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.67	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.42	B
Vest4		0.60
MutPred		0.86		Gain of catalytic residue at M1 (P = 0.0184);
MVP		0.93
ClinPred		0.25	T
GERP RS		3.0
Varity_R		0.47
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr3-128780584;