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GeneBe

rs1799990

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000311.5(PRNP):c.385A>G(p.Met129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,613,794 control chromosomes in the GnomAD database, including 89,542 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8515 hom., cov: 31)
Exomes 𝑓: 0.33 ( 81027 hom. )

Consequence

PRNP
NM_000311.5 missense

Scores

3
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13O:3

Conservation

PhyloP100: 0.542
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000311.5
BP4
Computational evidence support a benign effect (MetaRNN=0.0022065938).
BP6
Variant 20-4699605-A-G is Benign according to our data. Variant chr20-4699605-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 13397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699605-A-G is described in Lovd as [Likely_benign]. Variant chr20-4699605-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRNPNM_000311.5 linkuse as main transcriptc.385A>G p.Met129Val missense_variant 2/2 ENST00000379440.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRNPENST00000379440.9 linkuse as main transcriptc.385A>G p.Met129Val missense_variant 2/21 NM_000311.5 P1P04156-1
PRNPENST00000424424.2 linkuse as main transcriptc.385A>G p.Met129Val missense_variant 2/21 P1P04156-1
PRNPENST00000430350.2 linkuse as main transcriptc.385A>G p.Met129Val missense_variant 2/21 P1P04156-1
PRNPENST00000457586.2 linkuse as main transcriptc.385A>G p.Met129Val missense_variant 2/21 P1P04156-1

Frequencies

GnomAD3 genomes
AF:
0.329
AC:
49966
AN:
151820
Hom.:
8501
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.341
Gnomad AMI
AF:
0.385
Gnomad AMR
AF:
0.397
Gnomad ASJ
AF:
0.275
Gnomad EAS
AF:
0.0271
Gnomad SAS
AF:
0.251
Gnomad FIN
AF:
0.313
Gnomad MID
AF:
0.307
Gnomad NFE
AF:
0.340
Gnomad OTH
AF:
0.321
GnomAD3 exomes
AF:
0.309
AC:
77663
AN:
251266
Hom.:
13110
AF XY:
0.305
AC XY:
41416
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.340
Gnomad AMR exome
AF:
0.413
Gnomad ASJ exome
AF:
0.276
Gnomad EAS exome
AF:
0.0241
Gnomad SAS exome
AF:
0.255
Gnomad FIN exome
AF:
0.300
Gnomad NFE exome
AF:
0.338
Gnomad OTH exome
AF:
0.311
GnomAD4 exome
AF:
0.328
AC:
479223
AN:
1461854
Hom.:
81027
Cov.:
71
AF XY:
0.325
AC XY:
236250
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.336
Gnomad4 AMR exome
AF:
0.409
Gnomad4 ASJ exome
AF:
0.276
Gnomad4 EAS exome
AF:
0.0337
Gnomad4 SAS exome
AF:
0.258
Gnomad4 FIN exome
AF:
0.300
Gnomad4 NFE exome
AF:
0.344
Gnomad4 OTH exome
AF:
0.314
GnomAD4 genome
AF:
0.329
AC:
50030
AN:
151940
Hom.:
8515
Cov.:
31
AF XY:
0.327
AC XY:
24291
AN XY:
74278
show subpopulations
Gnomad4 AFR
AF:
0.341
Gnomad4 AMR
AF:
0.398
Gnomad4 ASJ
AF:
0.275
Gnomad4 EAS
AF:
0.0271
Gnomad4 SAS
AF:
0.251
Gnomad4 FIN
AF:
0.313
Gnomad4 NFE
AF:
0.340
Gnomad4 OTH
AF:
0.319
Alfa
AF:
0.335
Hom.:
9678
Bravo
AF:
0.336
TwinsUK
AF:
0.334
AC:
1240
ALSPAC
AF:
0.353
AC:
1359
ESP6500AA
AF:
0.341
AC:
1504
ESP6500EA
AF:
0.336
AC:
2889
ExAC
AF:
0.307
AC:
37316
Asia WGS
AF:
0.187
AC:
654
AN:
3478
EpiCase
AF:
0.331
EpiControl
AF:
0.336

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:13Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxOct 03, 2018This variant is associated with the following publications: (PMID: 23399523, 20711061, 12601712, 10360778, 10079068, 23405858, 22669942, 23209282, 24249784, 16897605, 11684342, 22912570, 12660994, 2783132, 26061765, 27910931, 30917570, 31182772, 24340298, 30817871, 19081515, 24620982, 32949544, 8105681) -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Huntington disease-like 1 Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Autism spectrum disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingGene Friend Way, National Innovation CenterJul 28, 2023Results in an increased risk of prion disease and long term memory issues (PMID 1677164, PMID 15987701). This gene encodes a protein that is active in the brain and other tissues. In our study, about 10% of patients diagnosed with Autism Spectrum Disorder carry this variant. However, due to high frequency of the variant in the Vietnamese population, the pathogenicity of this variant is uncertain. -
Gerstmann-Straussler-Scheinker syndrome;C0206042:Fatal familial insomnia;C0751254:Inherited Creutzfeldt-Jakob disease;C1847650:Spongiform encephalopathy with neuropsychiatric features;C1855588:Kuru, susceptibility to;C1864112:Huntington disease-like 1 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 22, 2021- -
Fatal familial insomnia Benign:1
Benign, criteria provided, single submitternot providedInstitute of Human Genetics, University Hospital of Duesseldorf-- -
Inherited prion disease Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Inherited Creutzfeldt-Jakob disease Benign:1
Likely benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Alzheimer disease, early-onset, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMNov 19, 2009- -
Prion disease, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMNov 19, 2009- -
Aphasia, primary progressive, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMNov 19, 2009- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Uncertain
0.020
Cadd
Benign
18
Dann
Benign
0.97
DEOGEN2
Benign
0.013
T;T;T;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.54
D
MetaRNN
Benign
0.0022
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
L;L;.;.
MutationTaster
Benign
0.18
P;P
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.66
N;N;N;N
REVEL
Uncertain
0.52
Sift
Uncertain
0.024
D;D;D;D
Sift4G
Benign
0.28
T;T;T;T
Polyphen
0.082
B;B;.;.
Vest4
0.061
MPC
0.52
ClinPred
0.0031
T
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.35
gMVP
0.78

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: rs1799990; hg19: chr20-4680251; COSMIC: COSV65173587; API