3-129061741-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_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

Scores

2
6
8

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.367
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 93 CDS bases. Genomic position: 129061832. Lost 0.174 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
GP9NM_000174.5 linkc.2T>C p.Met1? start_lost Exon 3 of 3 ENST00000307395.5 NP_000165.1 P14770
GP9XM_047447997.1 linkc.2T>C p.Met1? start_lost Exon 2 of 2 XP_047303953.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GP9ENST00000307395.5 linkc.2T>C p.Met1? start_lost Exon 3 of 3 1 NM_000174.5 ENSP00000303942.4 P14770

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
LINK: link

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; API