rs28933378
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000174.5(GP9):c.70T>C(p.Cys24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,852 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C24W) has been classified as Pathogenic.
Frequency
Consequence
NM_000174.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GP9 | NM_000174.5 | c.70T>C | p.Cys24Arg | missense_variant | 3/3 | ENST00000307395.5 | |
GP9 | XM_047447997.1 | c.70T>C | p.Cys24Arg | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GP9 | ENST00000307395.5 | c.70T>C | p.Cys24Arg | missense_variant | 3/3 | 1 | NM_000174.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000780 AC: 19AN: 243690Hom.: 0 AF XY: 0.000106 AC XY: 14AN XY: 132590
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1460698Hom.: 2 Cov.: 32 AF XY: 0.0000606 AC XY: 44AN XY: 726660
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74316
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys24 amino acid residue in GP9. Other variant(s) that disrupt this residue have been observed in individuals with GP9-related conditions (PMID: 21173099), which suggests that this may be a clinically significant amino acid residue. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 13533). This variant is also known as p.Cys8Arg. This missense change has been observed in individuals with Bernard-Soulier syndrome (PMID: 11167791, 21173099, 21699652, 23402648). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28933378, gnomAD 0.06%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 24 of the GP9 protein (p.Cys24Arg). - |
Bernard Soulier syndrome Pathogenic:3
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 11, 2020 | Variant summary: GP9 c.70T>C (p.Cys24Arg) results in a non-conservative amino acid change located in the Leucine-rich repeat N-terminal domain (IPR000372) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.8e-05 in 243690 control chromosomes. c.70T>C has been reported in the literature in multiple individuals (mostly homozygous) affected with Bernard Soulier Syndrome, and has been reported to be a common founder mutation (Sumitha_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 07, 2021 | - - |
Bernard-Soulier syndrome type C Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at