rs74315405
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000311.5(PRNP):c.593T>C(p.Phe198Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PRNP
NM_000311.5 missense
NM_000311.5 missense
Scores
7
7
4
Clinical Significance
Conservation
PhyloP100: 2.35
Genes affected
PRNP (HGNC:9449): (prion protein (Kanno blood group)) The protein encoded by this gene is a membrane glycosylphosphatidylinositol-anchored glycoprotein that tends to aggregate into rod-like structures. The encoded protein contains a highly unstable region of five tandem octapeptide repeats. This gene is found on chromosome 20, approximately 20 kbp upstream of a gene which encodes a biochemically and structurally similar protein to the one encoded by this gene. Mutations in the repeat region as well as elsewhere in this gene have been associated with Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler disease, Huntington disease-like 1, and kuru. An overlapping open reading frame has been found for this gene that encodes a smaller, structurally unrelated protein, AltPrp. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a strand (size 6) in uniprot entity PRIO_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000311.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.923
PP5
?
Variant 20-4699813-T-C is Pathogenic according to our data. Variant chr20-4699813-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699813-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRNP | NM_000311.5 | c.593T>C | p.Phe198Ser | missense_variant | 2/2 | ENST00000379440.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRNP | ENST00000379440.9 | c.593T>C | p.Phe198Ser | missense_variant | 2/2 | 1 | NM_000311.5 | P1 | |
PRNP | ENST00000424424.2 | c.593T>C | p.Phe198Ser | missense_variant | 2/2 | 1 | P1 | ||
PRNP | ENST00000430350.2 | c.593T>C | p.Phe198Ser | missense_variant | 2/2 | 1 | P1 | ||
PRNP | ENST00000457586.2 | c.593T>C | p.Phe198Ser | missense_variant | 2/2 | 1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2022 | Published functional studies demonstrate a damaging effect through thermodynamic instability and aggregation of the protein (Liemann et al., 1999; Singh et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8939199, 20301407, 16939293, 14761942, 21875156, 21689662, 20541558, 20932979, 21552571, 19680558, 19543376, 25959220, 29338055, 12372829, 7954833, 1363810, 1363809, 30877692, 31890235, 32560489, 31340582, 10079068, 8105481) - |
Huntington disease-like 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2017 | This sequence change replaces phenylalanine with serine at codon 198 of the PRNP protein (p.Phe198Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in a large and extensively studied family, referred to as the 'Indiana kindred', affected with Gerstmann-Straussler-Scheinker disease (GSS) (PMID: 1363810, 1363809). ClinVar contains an entry for this variant (Variation ID: 13401). Numerous experimental studies in vivo and in vitro have shown that this missense change (p.Phe198Ser) disrupts proper PRNP protein structure, folding, stability, and function (PMID: 16939293, 20541558, 25959220, 10079068, 12372829, 8939199). For these reasons, this variant has been classified as Pathogenic. - |
Gerstmann-Straussler-Scheinker syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 13, 2002 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.;.
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;.;.
Vest4
MutPred
Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);Gain of disorder (P = 0.0161);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at