3-129061508-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP7BA1

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

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.123
Variant links:
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]

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ACMG classification

Classification made for transcript

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
GP9NM_000174.5 linkc.-124C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 2 of 3 ENST00000307395.5 NP_000165.1 P14770
GP9NM_000174.5 linkc.-124C>T 5_prime_UTR_variant Exon 2 of 3 ENST00000307395.5 NP_000165.1 P14770
GP9XM_005247374.4 linkc.343C>T p.Arg115Trp missense_variant Exon 4 of 4 XP_005247431.2 P14770
GP9XM_047447997.1 linkc.-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
GP9ENST00000307395 linkc.-124C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 2 of 3 1 NM_000174.5 ENSP00000303942.4 P14770
GP9ENST00000307395 linkc.-124C>T 5_prime_UTR_variant Exon 2 of 3 1 NM_000174.5 ENSP00000303942.4 P14770

Frequencies

GnomAD3 genomes
AF:
0.00149
AC:
226
AN:
152146
Hom.:
0
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144100272; hg19: chr3-128780351; API