rs121918036

Positions:

• chr3-129061849-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000307395.5(GP9):​c.110A>G​(p.Asp37Gly) variant causes a missense 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GP9 ENST00000307395.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.242

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 9 ACMG points.

• PM1: In a chain Platelet glycoprotein IX (size 160) in uniprot entity GPIX_HUMAN there are 34 pathogenic changes around while only 3 benign (92%) in ENST00000307395.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 3-129061849-A-G is Pathogenic according to our data. Variant chr3-129061849-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13530.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-129061849-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP9	NM_000174.5	c.110A>G	p.Asp37Gly	missense_variant	3/3	ENST00000307395.5	NP_000165.1
GP9	XM_047447997.1	c.110A>G	p.Asp37Gly	missense_variant	2/2		XP_047303953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5	c.110A>G	p.Asp37Gly	missense_variant	3/3	1	NM_000174.5	ENSP00000303942	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bernard-Soulier syndrome type C Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.60	A
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.79
Sift	Benign	0.030	D
Sift4G	Uncertain	0.036	D
Polyphen		0.99	D
Vest4		0.72
MutPred		0.87		Loss of stability (P = 0.0792);
MVP		0.92
MPC		0.78
ClinPred		0.89	D
GERP RS		4.2
Varity_R		0.81
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs121918036; hg19: chr3-128780692;