rs74315402

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1PM2PP3_Moderate

The ENST00000379440.9(PRNP):​c.350C>T​(p.Ala117Val) 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. A117A) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PRNP
ENST00000379440.9 missense

Scores

6
7
6

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.66
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS1
Transcript ENST00000379440.9 (PRNP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2815837
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRNPNM_000311.5 linkuse as main transcriptc.350C>T p.Ala117Val missense_variant 2/2 ENST00000379440.9 NP_000302.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRNPENST00000379440.9 linkuse as main transcriptc.350C>T p.Ala117Val missense_variant 2/21 NM_000311.5 ENSP00000368752 P1P04156-1
PRNPENST00000424424.2 linkuse as main transcriptc.350C>T p.Ala117Val missense_variant 2/21 ENSP00000411599 P1P04156-1
PRNPENST00000430350.2 linkuse as main transcriptc.350C>T p.Ala117Val missense_variant 2/21 ENSP00000399376 P1P04156-1
PRNPENST00000457586.2 linkuse as main transcriptc.350C>T p.Ala117Val missense_variant 2/21 ENSP00000415284 P1P04156-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 02, 2017- -
Gerstmann-Straussler-Scheinker syndrome Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 1999- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.035
T;T;T;.
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Benign
0.66
D
LIST_S2
Pathogenic
1.0
.;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Benign
1.9
M;M;.;.
MutationTaster
Benign
0.52
A;A
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-1.3
N;N;N;N
REVEL
Uncertain
0.60
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0090
D;D;D;D
Polyphen
1.0
D;D;.;.
Vest4
0.84
MutPred
0.75
Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP
1.0
MPC
1.4
ClinPred
0.88
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.71
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs74315402; hg19: chr20-4680216; API