rs115005114

Variant names:

• chr3-129062280-C-T
• rs115005114
• NM_000174.5:c.*7C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000174.5(GP9):​c.*7C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00725 in 1,534,322 control chromosomes in the GnomAD database, including 301 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.027 (151 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (150 hom.)
• Consequence: GP9 NM_000174.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.250
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP9	NM_000174.5	c.*7C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000307395.5	NP_000165.1
GP9	XM_047447997.1	c.*7C>T		3_prime_UTR_variant	Exon 2 of 2		XP_047303953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395.5	c.*7C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_000174.5	ENSP00000303942.4

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4093 AN: 152118 Hom.: 151 Cov.: 33

Gnomad AFR AF: 0.0811

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.00994 AC: 1397 AN: 140486 AF XY: 0.00837

Gnomad AFR exome AF: 0.0841

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0418

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00509 AC: 7030 AN: 1382086 Hom.: 150 Cov.: 29 AF XY: 0.00487 AC XY: 3315 AN XY: 681206

African (AFR) AF: 0.0800 AC: 2495 AN: 31182

American (AMR) AF: 0.0126 AC: 445 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 1086 AN: 24962

East Asian (EAS) AF: 0.00 AC: 0 AN: 35670

South Asian (SAS) AF: 0.00112 AC: 88 AN: 78766

European-Finnish (FIN) AF: 0.0000211 AC: 1 AN: 47284

Middle Eastern (MID) AF: 0.0246 AC: 100 AN: 4060

European-Non Finnish (NFE) AF: 0.00199 AC: 2123 AN: 1067848

Other (OTH) AF: 0.0121 AC: 692 AN: 57128

GnomAD4 genome AF: 0.0269 AC: 4090 AN: 152236 Hom.: 151 Cov.: 33 AF XY: 0.0265 AC XY: 1974 AN XY: 74430

African (AFR) AF: 0.0808 AC: 3355 AN: 41526

American (AMR) AF: 0.0198 AC: 303 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 135 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 68006

Other (OTH) AF: 0.0289 AC: 61 AN: 2114

Alfa AF: 0.0114 Hom.: 15

Bravo AF: 0.0301

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bernard Soulier syndrome Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.72
DANN	Benign	0.82
PhyloP100		0.25
Mutation Taster		=100/0	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: rs115005114; hg19: chr3-128781123;