20-4699270-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001271561.3(PRNP):c.-40G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,978 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 1 hom. )

Consequence

PRNP
NM_001271561.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.841

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]

PRNP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16135344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRNP	NM_000311.5 link	c.50G>C	p.Ser17Thr	missense_variant	Exon 2 of 2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRNP	ENST00000379440.9 link	c.50G>C	p.Ser17Thr	missense_variant	Exon 2 of 2	1	NM_000311.5	ENSP00000368752.4	P04156-1
PRNP	ENST00000424424.2 link	c.50G>C	p.Ser17Thr	missense_variant	Exon 2 of 2	1		ENSP00000411599.2	P04156-1A2A2V1
PRNP	ENST00000430350.2 link	c.50G>C	p.Ser17Thr	missense_variant	Exon 2 of 2	1		ENSP00000399376.2	P04156-1
PRNP	ENST00000457586.2 link	c.50G>C	p.Ser17Thr	missense_variant	Exon 2 of 2	1		ENSP00000415284.2	P04156-1X6RKS3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000520

AC:

AN:

249988

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135462

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000886

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Huntington disease-like 1

Uncertain:1

Aug 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs368154579, gnomAD 0.008%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRNP protein function. ClinVar contains an entry for this variant (Variation ID: 871372). This variant has not been reported in the literature in individuals affected with PRNP-related conditions. This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 17 of the PRNP protein (p.Ser17Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;T;T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.046

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.78

.;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Uncertain

-0.028

MutationAssessor

Benign

1.1

L;L;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.52

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.11

T;T;T;T

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.0060

B;B;.;.

Vest4

0.068

MVP

1.0

MPC

1.1

ClinPred

0.055

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.056

gMVP

0.48

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over