NM_000174.5:c.466G>A

Variant names:

• chr3-129062205-G-A
• rs3796130
• NM_000174.5:c.466G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PS3_Supporting BA1 BP4

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
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 2.80
• Publications: 10 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: 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.

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.466G>A	p.Ala156Thr	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.466G>A	p.Ala156Thr	missense	Exon 3 of 3	ENSP00000303942.4
	GP9	ENST00000900754.1		c.466G>A	p.Ala156Thr	missense	Exon 3 of 3	ENSP00000570813.1
	GP9	ENST00000900755.1		c.466G>A	p.Ala156Thr	missense	Exon 2 of 2	ENSP00000570814.1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2492 AN: 152196 Hom.: 168 Cov.: 33

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

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.: 32 AF XY: 0.0125 AC XY: 8786 AN XY: 700190

African (AFR) AF: 0.00159 AC: 52 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: 13 AN: 4636

European-Non Finnish (NFE) AF: 0.000532 AC: 581 AN: 1091994

Other (OTH) AF: 0.0209 AC: 1225 AN: 58618

GnomAD4 genome AF: 0.0163 AC: 2486 AN: 152314 Hom.: 168 Cov.: 33 AF XY: 0.0183 AC XY: 1364 AN XY: 74476

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: 30 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: 89 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68038

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.00573 Hom.: 13

Bravo AF: 0.0215

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0321 AC: 3594

Asia WGS AF: 0.119 AC: 411 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Bernard Soulier syndrome (3)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Benign	0.15	T
Sift4G	Benign	0.077	T
Polyphen		0.69	P
Vest4		0.080
MPC		0.23
ClinPred		0.015	T
GERP RS		3.0
Varity_R		0.033
gMVP		0.49
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3796130; hg19: chr3-128781048; COSMIC: COSV107322380;