chr3-129061921-A-G

Variant names:

• chr3-129061921-A-G
• rs5030764
• NM_000174.5:c.182A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1_Strong PM3 PS3_Supporting PP4_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The c.182A>G (p.Asn61Ser) variant in GP9 is known for being frequently reported in BSS patients of European ancestry. It has been detected in at least 30 probands with Bernard-Soulier syndrome. At least 16 probands included in this curation have origin in Central or Northern Europe (France, Finland, Sweden, Germany, Belgium, Austria, and England). The literature supports the hypothesis of Koskela et al., which suggests that the c.182A>G (p.Asn61Ser) variant is an ancient founder mutation in this region (PMID:10227459). At least one patient with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome and with full gene sequencing and del/dup analysis of all BSS genes (PP4_moderate, Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, NSW, Australia). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. At least 2 of the probands included in this curation were homozygous for the variant and were confirmed to have the variants in trans (PM3; PMIDs: 8049428, 14510954, 8856096, 10227459, 11297032). The variant has been reported to segregate with Bernard-Soulier syndrome in the proband (meeting PP4) plus 3 (>2) affected family members, all with the homozygous genotype. (PP1_strong; PMID:19404517). The Grp max filtering allele frequency in gnomAD v4.1 is 0.0008047 (1001/1179870 alleles) in the European (Non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0007 for GP9), and therefore meets this criterion (BS1), however since this is a known founder variant BS1 will not be applied. The computational predictor REVEL gives a score of 0.721, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). A zebrafish model made by deleting 17bps in exon 2 of gp9 using CRISPR-Cas9 demonstrated thrombocytopenia and abnormal bleeding. The thrombocytopenia phenotype in the zebrafish was rescued using a wild-type copy of human GP9. The human copy of GP9 containing the c.182A>G variant failed to rescue the same phenotype, indicating that this variant impacts protein function (PMID:34407604)(PS3_Supporting).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM3, PP3, PP4_moderate, PP1_Strong, PS3_Supporting. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA123173/MONDO:0009276/083

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: GP9 NM_000174.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:22 O:1
• Conservation: PhyloP100: 3.62
• Publications: 19 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000174.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP9	NM_000174.5	MANE Select	c.182A>G	p.Asn61Ser	missense	Exon 3 of 3	NP_000165.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP9	ENST00000307395.5	TSL:1 MANE Select	c.182A>G	p.Asn61Ser	missense	Exon 3 of 3	ENSP00000303942.4
	GP9	ENST00000900754.1		c.182A>G	p.Asn61Ser	missense	Exon 3 of 3	ENSP00000570813.1
	GP9	ENST00000900755.1		c.182A>G	p.Asn61Ser	missense	Exon 2 of 2	ENSP00000570814.1

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152164 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000479 AC: 119 AN: 248302 AF XY: 0.000498

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 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.: 0 Cov.: 32 AF XY: 0.000646 AC XY: 470 AN XY: 727094

African (AFR) AF: 0.000149 AC: 5 AN: 33472

American (AMR) AF: 0.0000895 AC: 4 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.000864 AC: 46 AN: 53214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000835 AC: 928 AN: 1111866

Other (OTH) AF: 0.000696 AC: 42 AN: 60384

GnomAD4 genome AF: 0.000697 AC: 106 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.000592 AC XY: 44 AN XY: 74336

African (AFR) AF: 0.000386 AC: 16 AN: 41444

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68004

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000876 Hom.: 0

Bravo AF: 0.000627

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000634 AC: 77

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Bernard Soulier syndrome (10)
8	-	-	not provided (8)
2	-	-	Macrothrombocytopenia (2)
1	-	-	Bernard-Soulier syndrome type C (1)
1	-	-	GP9-related disorder (1)
1	-	-	Thrombocytopenia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		3.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.94
MPC		0.62
ClinPred		0.15	T
GERP RS		4.2
Varity_R		0.79
gMVP		0.92
Mutation Taster		=61/39	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs5030764; hg19: chr3-128780764;