chr20-4699758-G-A

Position:

chr20-4699758-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PP5_StrongBP4BS1_Supporting

The NM_000311.5(PRNP):c.538G>A(p.Val180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,614,004 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 other (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 1 hom. )

Consequence

PRNP
NM_000311.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 3.18

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000311.5

PP5

Variant 20-4699758-G-A is Pathogenic according to our data. Variant chr20-4699758-G-A is described in ClinVar as [other]. Clinvar id is 13405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=2, not_provided=1, Pathogenic_low_penetrance=1}. Variant chr20-4699758-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.29018027). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000903 (132/1461882) while in subpopulation EAS AF= 0.00234 (93/39700). AF 95% confidence interval is 0.00196. There are 1 homozygotes in gnomad4_exome. There are 73 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5 linkuse as main transcript	c.538G>A	p.Val180Ile	missense_variant	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9 linkuse as main transcript	c.538G>A	p.Val180Ile	missense_variant	2/2	1	NM_000311.5	P1	P04156-1
PRNP	ENST00000424424.2 linkuse as main transcript	c.538G>A	p.Val180Ile	missense_variant	2/2	1		P1	P04156-1
PRNP	ENST00000430350.2 linkuse as main transcript	c.538G>A	p.Val180Ile	missense_variant	2/2	1		P1	P04156-1
PRNP	ENST00000457586.2 linkuse as main transcript	c.538G>A	p.Val180Ile	missense_variant	2/2	1		P1	P04156-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000967

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251468

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000903

AC:

132

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00234

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000969

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inherited Creutzfeldt-Jakob disease

Pathogenic:2Other:1

Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 10, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	One of the five most common variants that account for 85% of genetic prion disease. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 24, 2021

- -

Inherited prion disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 05, 2019

The PRNP c.538G>A (p.Val180Ile) missense variant is the most common pathogenic variant found in association with Creutzfeldt-Jacob disease (CJD) (Lee et al. 2016). Across a selection of the available literature, the p.Val180Ile variant has been identified in a heterozygous state in at least 194 individuals with prion diseases and in one individual with CJD (Kitamoto et al. 1993; Chasseigneaux et al. 2006; Yang et al. 2010; Yoshida et al. 2010; Moe Lee et al. 2012; Higuma et al. 2013; Shi et al. 2014; Qina et al. 2014). Qina et al. (2014) also noted that only 11 out of 186 Japanese patients with the p.Val180Ile variant had a family history of dementia, suggesting that this variant may have reduced penetrance. Patients carrying the p.Val180Ile variant have a later onset of disease (late 70s), with a slower progression and a lower possibility of developing myoclonus, cerebellar, pyramidal signs and visual disturbance as compared to classic CJD presentation (Qina et al. 2014). The p.Val180Ile variant was absent from 159 control individuals without neurological diseases from the above studies but is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. This frequency is unexpectedly high given the expected prevalence of this condition. Due to the large number of clinical cases with genetic prion diseases carrying this variant, this variant is classified as pathogenic for genetic prion diseases. However, the specific implications of this variant are somewhat uncertain given the later onset, milder presentation, and high population frequency that have been associated with this variant. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Huntington disease-like 1

Pathogenic:1

Pathogenic, low penetrance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 180 of the PRNP protein (p.Val180Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of Creutzfeldt-Jakob syndrome or prion disease (PMID: 8461023, 21269331, 22999564, 23555862, 25482600, 26791950). A large case control study reported that individuals carrying this variant have a life-time risk of developing prion disease of approximately 1% (PMID: 26791950). ClinVar contains an entry for this variant (Variation ID: 13405). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRNP function (PMID: 17494694, 23132868, 23527023, 29382530). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the PRNP gene, it has been classified as Pathogenic (low penetrance). -

Gerstmann-Straussler-Scheinker syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013405, PMID:8461023, PS1_S). TIn silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.624, 3CNET: 0.858, PP3_P). A missense variant is a common mechanism associated with Gerstmann-Straussler disease (PP2_P). herefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T;T;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.92

.;D;D;D

M_CAP

Benign

0.063

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.6

M;M;.;.

MutationTaster

Benign

0.74

A;A

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.11

N;N;N;N

REVEL

Uncertain

0.62

Sift

Uncertain

0.013

D;D;D;D

Sift4G

Uncertain

0.037

D;D;D;T

Polyphen

0.031

B;B;.;.

Vest4

0.23

MVP

1.0

MPC

0.92

ClinPred

0.24

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.83

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