rs144100272

Variant names:

• chr3-129061508-C-T
• rs144100272
• NM_000174.5:c.-124C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP7 BA1

This summary comes from the ClinGen Evidence Repository: The c.-124C>T variant in GP9 is a non-coding variant which located upstream of the 5' UTR. It was identified through an ICLS predisposition screen in an ostensibly healthy population. To date, this variant has not been reported in any patients with BSS. The c.-124C>T variant is an intronic variant that is not predicted by SpliceAI to impact splicing (acceptor gain score of 0.1 which is less than the VCEP threshold of <0.2). In addition, it occurs at a nucleotide that is not highly conserved as shown by phyloP score of 0.314583 (<1.5) (BP7). The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.004120 (248/54052 alleles) in the African/African American population, which is higher than the ClinGen PD VCEP threshold (>0.001), and therefore meets this criterion (BA1).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA82551874/MONDO:0009276/083

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: GP9 NM_000174.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.123

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 -9 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP9	NM_000174.5	c.-124C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3	ENST00000307395.5	NP_000165.1
GP9	NM_000174.5	c.-124C>T		5_prime_UTR_variant	Exon 2 of 3	ENST00000307395.5	NP_000165.1
GP9	XM_005247374.4	c.343C>T	p.Arg115Trp	missense_variant	Exon 4 of 4		XP_005247431.2
GP9	XM_047447997.1	c.-12-220C>T		intron_variant	Intron 1 of 1		XP_047303953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP9	ENST00000307395	c.-124C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3	1	NM_000174.5	ENSP00000303942.4
GP9	ENST00000307395	c.-124C>T		5_prime_UTR_variant	Exon 2 of 3	1	NM_000174.5	ENSP00000303942.4

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.000428 AC: 192 AN: 448578 Hom.: 0 Cov.: 3 AF XY: 0.000393 AC XY: 93 AN XY: 236424

Gnomad4 AFR exome AF: 0.00591

Gnomad4 AMR exome AF: 0.000983

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000137

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74446

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00186

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bernard Soulier syndrome Uncertain:1

Feb 02, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.8
DANN	Benign	0.50

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: rs144100272; hg19: chr3-128780351;