chr3-129061809-T-C

Position:

chr3-129061809-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000174.5(GP9):c.70T>C(p.Cys24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,852 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C24W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 2 hom. )

Consequence

GP9
NM_000174.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.642

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]

GP9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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 NM_000174.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-129061811-T-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 3-129061809-T-C is Pathogenic according to our data. Variant chr3-129061809-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129061809-T-C is described in Lovd as [Likely_pathogenic]. Variant chr3-129061809-T-C is described in Lovd as [Pathogenic]. Variant chr3-129061809-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP9	NM_000174.5 linkuse as main transcript	c.70T>C	p.Cys24Arg	missense_variant	3/3	ENST00000307395.5
GP9	XM_047447997.1 linkuse as main transcript	c.70T>C	p.Cys24Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP9	ENST00000307395.5 linkuse as main transcript	c.70T>C	p.Cys24Arg	missense_variant	3/3	1	NM_000174.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000780

AC:

AN:

243690

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

132590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000593

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000918

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1460698

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

726660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000685

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000599

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 09, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys24 amino acid residue in GP9. Other variant(s) that disrupt this residue have been observed in individuals with GP9-related conditions (PMID: 21173099), which suggests that this may be a clinically significant amino acid residue. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 13533). This variant is also known as p.Cys8Arg. This missense change has been observed in individuals with Bernard-Soulier syndrome (PMID: 11167791, 21173099, 21699652, 23402648). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28933378, gnomAD 0.06%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 24 of the GP9 protein (p.Cys24Arg). -

Bernard Soulier syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 07, 2021	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2020	Variant summary: GP9 c.70T>C (p.Cys24Arg) results in a non-conservative amino acid change located in the Leucine-rich repeat N-terminal domain (IPR000372) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.8e-05 in 243690 control chromosomes. c.70T>C has been reported in the literature in multiple individuals (mostly homozygous) affected with Bernard Soulier Syndrome, and has been reported to be a common founder mutation (Sumitha_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Bernard-Soulier syndrome type C

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.010

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-9.9

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.78

MVP

0.98

MPC

0.93

ClinPred

0.96

GERP RS

4.2

Varity_R

0.87

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over