rs6069

chr3-129061871-G-Achr3-129061871-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000174.5(GP9):c.132G>A(p.Thr44=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,612,758 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (231 hom., cov: 33)
  • Exomes 𝑓: 0.010 (530 hom.)
• Consequence: GP9 NM_000174.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.51

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-129061871-G-A is Benign according to our data. Variant chr3-129061871-G-A is described in ClinVar as [Benign]. Clinvar id is 255471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP9	NM_000174.5	c.132G>A	p.Thr44=	synonymous_variant	3/3	ENST00000307395.5
GP9	XM_047447997.1	c.132G>A	p.Thr44=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP9	ENST00000307395.5	c.132G>A	p.Thr44=	synonymous_variant	3/3	1	NM_000174.5	P1

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5438 AN: 152158 Hom.: 230 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.0703

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.0238 AC: 5799 AN: 243794 Hom.: 216 AF XY: 0.0241 AC XY: 3194 AN XY: 132678

Gnomad AFR exome AF: 0.0997

Gnomad AMR exome AF: 0.00491

Gnomad ASJ exome AF: 0.00192

Gnomad EAS exome AF: 0.0810

Gnomad SAS exome AF: 0.0664

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.0101 AC: 14694 AN: 1460482 Hom.: 530 Cov.: 32 AF XY: 0.0115 AC XY: 8331 AN XY: 726590

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.00551

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0625

Gnomad4 SAS exome AF: 0.0634

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0358 AC: 5453 AN: 152276 Hom.: 231 Cov.: 33 AF XY: 0.0367 AC XY: 2731 AN XY: 74460

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0745

Gnomad4 SAS AF: 0.0702

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.00432 Hom.: 13

Bravo AF: 0.0372

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00125

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Bernard Soulier syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.1
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6069; hg19: chr3-128780714; COSMIC: COSV56624952;