rs1799990

chr20-4699605-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13 O:3
• Conservation: PhyloP100: 0.542

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]

ACMG classification

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
PRNP	NM_000311.5	c.385A>G	p.Met129Val	missense_variant	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.385A>G	p.Met129Val	missense_variant	2/2	1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.385A>G	p.Met129Val	missense_variant	2/2	1		P1
PRNP	ENST00000430350.2	c.385A>G	p.Met129Val	missense_variant	2/2	1		P1
PRNP	ENST00000457586.2	c.385A>G	p.Met129Val	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49966 AN: 151820 Hom.: 8501 Cov.: 31

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

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

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

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:1 Benign:13 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2018	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

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Autism spectrum disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Gene Friend Way, National Innovation Center

Jul 28, 2023

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

Fatal familial insomnia Benign:1

Benign, criteria provided, single submitter

not provided

Institute of Human Genetics, University Hospital of Duesseldorf

-

- -

Inherited prion disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Inherited Creutzfeldt-Jakob disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

PRION DISEASE, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 19, 2009

- -

ALZHEIMER DISEASE, EARLY-ONSET, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 19, 2009

- -

APHASIA, PRIMARY PROGRESSIVE, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 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

Other links and lift over

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