NM_000311.5:c.385A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 13/20 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

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:14O: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]

PRNP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 rank	MANE	Protein	UniProt
PRNP	NM_000311.5 link	c.385A>G	p.Met129Val	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.385A>G	p.Met129Val	missense_variant	Exon 2 of 2	1	NM_000311.5	ENSP00000368752.4	P04156-1
PRNP	ENST00000424424.2 link	c.385A>G	p.Met129Val	missense_variant	Exon 2 of 2	1		ENSP00000411599.2	P04156-1A2A2V1
PRNP	ENST00000430350.2 link	c.385A>G	p.Met129Val	missense_variant	Exon 2 of 2	1		ENSP00000399376.2	P04156-1
PRNP	ENST00000457586.2 link	c.385A>G	p.Met129Val	missense_variant	Exon 2 of 2	1		ENSP00000415284.2	P04156-1X6RKS3

Frequencies

GnomAD3 genomes

AF:

0.329

AC:

49966

AN:

151820

Hom.:

8501

Cov.:

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.:

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.:

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:14Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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) -

Huntington disease-like 1

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autism spectrum disorder

Uncertain:1

Jul 28, 2023

Gene Friend Way, National Innovation Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Results 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

Jul 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fatal familial insomnia

Benign:1

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inherited Creutzfeldt-Jakob disease

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited prion disease

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

PRION DISEASE, SUSCEPTIBILITY TO

Other:1

Nov 19, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

ALZHEIMER DISEASE, EARLY-ONSET, SUSCEPTIBILITY TO

Other:1

Nov 19, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

APHASIA, PRIMARY PROGRESSIVE, SUSCEPTIBILITY TO

Other:1

Nov 19, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

0.020

CADD

Benign

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

LIST_S2

Benign

0.78

.;T;T;T

MetaRNN

Benign

0.0022

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L;.;.

PrimateAI

Benign

0.45

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

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.

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