3-129061921-A-G

Position:

chr3-129061921-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_000174.5(GP9):c.182A>G(p.Asn61Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000701 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 0 hom. )

Consequence

GP9
NM_000174.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 3.62

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 12 ACMG points.

PM1

In a chain Platelet glycoprotein IX (size 160) in uniprot entity GPIX_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_000174.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-129061921-A-G is Pathogenic according to our data. Variant chr3-129061921-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129061921-A-G is described in Lovd as [Likely_pathogenic]. Variant chr3-129061921-A-G is described in Lovd as [Pathogenic]. Variant chr3-129061921-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP9	NM_000174.5 linkuse as main transcript	c.182A>G	p.Asn61Ser	missense_variant	3/3	ENST00000307395.5	NP_000165.1
GP9	XM_047447997.1 linkuse as main transcript	c.182A>G	p.Asn61Ser	missense_variant	2/2		XP_047303953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5 linkuse as main transcript	c.182A>G	p.Asn61Ser	missense_variant	3/3	1	NM_000174.5	ENSP00000303942	P1

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000479

AC:

119

AN:

248302

Hom.:

AF XY:

0.000498

AC XY:

AN XY:

134624

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.000936

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000701

AC:

1025

AN:

1461474

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

470

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000864

Gnomad4 NFE exome

AF:

0.000835

Gnomad4 OTH exome

AF:

0.000696

GnomAD4 genome

AF:

0.000697

AC:

106

AN:

152164

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000876

Hom.:

Bravo

AF:

0.000627

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000634

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000652

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bernard Soulier syndrome

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 28, 2017	The GP9 c.182A>G (p.Asn61Ser) missense variant has been reported in four studies in which it is found in a total of ten individuals with bleeding abnormalities characteristic of Bernard-Soulier syndrome, including in six in a homozygous state and in four (including three siblings) in a compound heterozygous state (Wright et al. 1993; Clemetson et al. 1994; Sachs et al. 2003; Bragadottir et al. 2015). The variant was also found in a heterozygous state in six unaffected family members. The p.Asn61Ser variant was absent from 208 control alleles and is reported at a frequency of 0.001073 in the non-Finnish European population of the Exome Aggregation Consortium. Based on the evidence, the p.Asn61Ser variant is classified as pathogenic for Bernard-Soulier syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 21, 2016	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 13, 2021	- -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 61 of the GP9 protein (p.Asn61Ser). This variant is present in population databases (rs5030764, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with Bernard-Soulier syndrome (PMID: 8481514, 14510954, 25370924, 28131619, 28765788). It has also been observed to segregate with disease in related individuals. This variant is also known as Asn45Ser. ClinVar contains an entry for this variant (Variation ID: 13529). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25370924, 14510954, 8049428, 31064749, 8481514, 27934591, 28131619, 28765788, 28960434, 30431218, 31980526, 32581362, 31589614, 33553065, 24934643) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	GP9: PM3:Very Strong, PP1:Moderate, PM2:Supporting, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 27, 2022	- -

Macrothrombocytopenia

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Mar 22, 2019	- -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

Bernard-Soulier syndrome type C

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

GP9-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

The GP9 c.182A>G variant is predicted to result in the amino acid substitution p.Asn61Ser. This variant, also described as p.Asn45Ser in the literature, has been reported in the homozygous or compound heterozygous states in multiple individuals with Bernard-Soulier syndrome (Wright et al. 1993. PubMed ID: 8481514; Clemetson et al. 1994. PubMed ID: 8049428; Liang et al. 2005. PubMed ID: 16268478; Romasko et al. 2018. PubMed ID: 28960434; Saes et al. 2019. PubMed ID: 30431218). This variant is reported in 0.095% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Thrombocytopenia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.86

MetaRNN

Uncertain

0.53

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MVP

0.94

MPC

0.62

ClinPred

0.15

GERP RS

4.2

Varity_R

0.79

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 1

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