rs121918037
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000307395.5(GP9):āc.212T>Cā(p.Phe71Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F71C) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000307395.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GP9 | NM_000174.5 | c.212T>C | p.Phe71Ser | missense_variant | 3/3 | ENST00000307395.5 | NP_000165.1 | |
GP9 | XM_047447997.1 | c.212T>C | p.Phe71Ser | missense_variant | 2/2 | XP_047303953.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GP9 | ENST00000307395.5 | c.212T>C | p.Phe71Ser | missense_variant | 3/3 | 1 | NM_000174.5 | ENSP00000303942 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461534Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727106
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74378
ClinVar
Submissions by phenotype
Bernard Soulier syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 25, 2022 | Variant summary: GP9 c.212T>C (p.Phe71Ser) results in a non-conservative amino acid change located in the Leucine-rich repeat (IPR001611) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248306 control chromosomes (gnomAD). c.212T>C has been reported in the literature in multiple homozygous individuals affected with Bernard Soulier Syndrome (Noris_1997, Suzuki_1997, Sumitha_2011, Sanchez-Guiu_2014, Savoia_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, however it is suggested that disruption of the the leucine-rich repeat motif impairs surface expression of the GPIb/IX/V complex (Sumitha_2011, Suzuki_1997). Other substitutions at this codon (Phe>Cys) have also been found to impact surface GPIb/IX/V expression (Sumitha_2011). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and the other as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Bernard-Soulier syndrome type C Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1997 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 21, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 71 of the GP9 protein (p.Phe71Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Bernard-Soulier Syndrome and/or Bernard-Soulier syndrome (PMID: 9163595, 21699652, 25539746, 28395735, 29636940). This variant is also known as Phe55Ser. ClinVar contains an entry for this variant (Variation ID: 13531). 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. This variant disrupts the p.Phe71 amino acid residue in GP9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21699652; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Macrothrombocytopenia Pathogenic:1
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at