rs3796130

Positions:

• chr3-129062205-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000174.5(GP9):​c.466G>A​(p.Ala156Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,566,356 control chromosomes in the GnomAD database, including 1,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (168 hom., cov: 33)
  • Exomes 𝑓: 0.012 (1339 hom.)
• Consequence: GP9 NM_000174.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.80

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]

ACMG classification

Verdict is Benign. Variant got -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054330826).
• BP6: Variant 3-129062205-G-A is Benign according to our data. Variant chr3-129062205-G-A is described in ClinVar as [Benign]. Clinvar id is 196227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP9	NM_000174.5	c.466G>A	p.Ala156Thr	missense_variant	3/3	ENST00000307395.5	NP_000165.1
GP9	XM_047447997.1	c.466G>A	p.Ala156Thr	missense_variant	2/2		XP_047303953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5	c.466G>A	p.Ala156Thr	missense_variant	3/3	1	NM_000174.5	ENSP00000303942	P1

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

GnomAD3 exomes AF: 0.0471 AC: 7662 AN: 162702 Hom.: 626 AF XY: 0.0411 AC XY: 3682 AN XY: 89656

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 SAS exome AF: 0.0308

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

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.223

Gnomad4 SAS exome AF: 0.0308

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.000532

Gnomad4 OTH exome AF: 0.0209

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

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.0547

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.0306

Gnomad4 FIN AF: 0.00838

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.0175

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 20981092, 11758225, 27884173, 27291889) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -

Bernard Soulier syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P
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

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

Other links and lift over

dbSNP: rs3796130; hg19: chr3-128781048;