chr3-129062205-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PS3_SupportingBA1BP4

This summary comes from the ClinGen Evidence Repository: The c.466G>A (p.Ala156Thr) variant in GP9 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 156. At least one patient (Case in PMID:15351858 or internal) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which is consistent with Bernard-Soulier syndrome, however this variant has a Grpmax Filtering allele frequency in gnomAD v4.1 is 0.2194 (based on 9530/42710 alleles) in the East Asian population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.187, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP9 function and splicing predictor SpliceAI predicts no impact on splicing with delta scores of 0.00 (BP4). Surface expression of GPIBa and GP9 measured by flow cytometry in CHO cells in cells transiently co-transfected with the c.466G>A variant and wild type GP1a and GP1b showed decreased expression at very low (<25%) WT levels, indicating that this variant impacts protein function (PMID:15351858)(PS3_supporting). In summary with BP4 (-1), BA1, PS3_supporting (+1), the other criteria cancel out and BA1 alone provides a Benign classification, ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP. LINK:https://erepo.genome.network/evrepo/ui/classification/CA202222/MONDO:0009276/083

Frequency

Genomes: 𝑓 0.016 ( 168 hom., cov: 33)

Exomes 𝑓: 0.012 ( 1339 hom. )

Consequence

GP9
NM_000174.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 2.80

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

Bernard-Soulier syndrome
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

GP9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP9	NM_000174.5 link	c.466G>A	p.Ala156Thr	missense_variant	Exon 3 of 3	ENST00000307395.5	NP_000165.1	P14770
GP9	XM_047447997.1 link	c.466G>A	p.Ala156Thr	missense_variant	Exon 2 of 2		XP_047303953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5 link	c.466G>A	p.Ala156Thr	missense_variant	Exon 3 of 3	1	NM_000174.5	ENSP00000303942.4		P14770

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

2492

AN:

152196

Hom.:

168

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0547

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.0310

Gnomad FIN

AF:

0.00838

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0471

AC:

7662

AN:

162702

AF XY:

0.0411

show subpopulations

Gnomad AFR exome

AF:

0.00353

Gnomad AMR exome

AF:

0.118

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.244

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.00130

Gnomad OTH exome

AF:

0.0244

GnomAD4 exome

AF:

0.0125

AC:

17669

AN:

1414042

Hom.:

1339

Cov.:

AF XY:

0.0125

AC XY:

8786

AN XY:

700190

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

32648

American (AMR)

AF:

0.109

AC:

4198

AN:

38686

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

277

AN:

25302

East Asian (EAS)

AF:

0.223

AC:

8373

AN:

37560

South Asian (SAS)

AF:

0.0308

AC:

2505

AN:

81380

European-Finnish (FIN)

AF:

0.0103

AC:

445

AN:

43218

Middle Eastern (MID)

AF:

0.00280

AC:

AN:

4636

European-Non Finnish (NFE)

AF:

0.000532

AC:

581

AN:

1091994

Other (OTH)

AF:

0.0209

AC:

1225

AN:

58618

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1053

2106

3158

4211

5264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

228

456

684

912

1140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0163

AC:

2486

AN:

152314

Hom.:

168

Cov.:

AF XY:

0.0183

AC XY:

1364

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00277

AC:

115

AN:

41576

American (AMR)

AF:

0.0547

AC:

837

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3470

East Asian (EAS)

AF:

0.225

AC:

1157

AN:

5150

South Asian (SAS)

AF:

0.0306

AC:

148

AN:

4832

European-Finnish (FIN)

AF:

0.00838

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00107

AC:

AN:

68038

Other (OTH)

AF:

0.0175

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

113

226

339

452

565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00573

Hom.:

Bravo

AF:

0.0215

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0321

AC:

3594

Asia WGS

AF:

0.119

AC:

411

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20981092, 11758225, 27884173, 27291889) -

Bernard Soulier syndrome

Benign:3

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone, for Bernard Soulier syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 11, 2025

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.466G>A (p.Ala156Thr) variant in GP9 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 156. At least one patient (Case in PMID:15351858 or internal) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome. Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which is consistent with Bernard-Soulier syndrome, however this variant has a Grpmax Filtering allele frequency in gnomAD v4.1 is 0.2194 (based on 9530/42710 alleles) in the East Asian population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.187, which is below the ClinGen PD VCEP threshold of <0.290 and predicts no damaging effect on GP9 function and splicing predictor SpliceAI predicts no impact on splicing with delta scores of 0.00 (BP4). Surface expression of GPIBa and GP9 measured by flow cytometry in CHO cells in cells transiently co-transfected with the c.466G>A variant and wild type GP1a and GP1b showed decreased expression at very low (<25%) WT levels, indicating that this variant impacts protein function (PMID:15351858)(PS3_supporting). In summary with BP4 (-1), BA1, PS3_supporting (+1), the other criteria cancel out and BA1 alone provides a Benign classification, ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP. -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 14, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.12

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

2.8

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

REVEL

Benign

0.19

Sift

Benign

0.15

Sift4G

Benign

0.077

Polyphen

0.69

Vest4

0.080

MPC

0.23

ClinPred

0.015

GERP RS

3.0

Varity_R

0.033

gMVP

0.49

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over