20-4699732-A-G

Position:

chr20-4699732-A-G

Variant summary

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

The ENST00000379440.9(PRNP):c.512A>G(p.Asn171Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,614,052 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 50 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 49 hom. )

Consequence

PRNP
ENST00000379440.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: -0.149

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 -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 0 benign, 4 uncertain in ENST00000379440.9

BP4

Computational evidence support a benign effect (MetaRNN=0.01805228).

BP6

Variant 20-4699732-A-G is Benign according to our data. Variant chr20-4699732-A-G is described in ClinVar as [Benign]. Clinvar id is 13408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699732-A-G is described in Lovd as [Likely_benign]. Variant chr20-4699732-A-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5 linkuse as main transcript	c.512A>G	p.Asn171Ser	missense_variant	2/2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9 linkuse as main transcript	c.512A>G	p.Asn171Ser	missense_variant	2/2	1	NM_000311.5	ENSP00000368752	P1	P04156-1
PRNP	ENST00000424424.2 linkuse as main transcript	c.512A>G	p.Asn171Ser	missense_variant	2/2	1		ENSP00000411599	P1	P04156-1
PRNP	ENST00000430350.2 linkuse as main transcript	c.512A>G	p.Asn171Ser	missense_variant	2/2	1		ENSP00000399376	P1	P04156-1
PRNP	ENST00000457586.2 linkuse as main transcript	c.512A>G	p.Asn171Ser	missense_variant	2/2	1		ENSP00000415284	P1	P04156-1

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

2266

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0517

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.00377

AC:

949

AN:

251490

Hom.:

AF XY:

0.00282

AC XY:

383

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0525

Gnomad AMR exome

AF:

0.00225

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00146

AC:

2131

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

890

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0524

Gnomad4 AMR exome

AF:

0.00320

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.00296

GnomAD4 genome

AF:

0.0150

AC:

2277

AN:

152160

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1070

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0518

Gnomad4 AMR

AF:

0.00634

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.00348

Hom.:

Bravo

AF:

0.0170

ESP6500AA

AF:

0.0474

AC:

209

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00496

AC:

602

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2018	This variant is associated with the following publications: (PMID: 22995991, 22717776, 20981092, 9384372) -

Spongiform encephalopathy with neuropsychiatric features

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Feb 01, 2012

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

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

- -

Inherited prion disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Huntington disease-like 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.35

DANN

Benign

0.95

DEOGEN2

Benign

0.18

T;T;T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.87

.;D;D;D

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.98

L;L;.;.

MutationTaster

Benign

0.00044

A;A

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.060

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.085

T;T;T;T

Sift4G

Benign

0.60

T;T;T;T

Polyphen

0.018

B;B;.;.

Vest4

0.056

MVP

0.98

MPC

0.39

ClinPred

0.0014

GERP RS

-0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.67

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