rs8124214

Positions:

chr20-4699571-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000311.5(PRNP):c.351A>G(p.Ala117Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,613,982 control chromosomes in the GnomAD database, including 987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 193 hom., cov: 32)

Exomes 𝑓: 0.030 ( 794 hom. )

Consequence

PRNP
NM_000311.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.16

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 20-4699571-A-G is Benign according to our data. Variant chr20-4699571-A-G is described in ClinVar as [Benign]. Clinvar id is 338650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699571-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0815 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.351A>G	p.Ala117Ala	synonymous_variant	2/2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PRNP	ENST00000379440.9 linkuse as main transcript	c.351A>G	p.Ala117Ala	synonymous_variant	2/2	1	NM_000311.5	ENSP00000368752.4	P04156-1
PRNP	ENST00000424424.2 linkuse as main transcript	c.351A>G	p.Ala117Ala	synonymous_variant	2/2	1		ENSP00000411599.2	P04156-1A2A2V1
PRNP	ENST00000430350.2 linkuse as main transcript	c.351A>G	p.Ala117Ala	synonymous_variant	2/2	1		ENSP00000399376.2	P04156-1
PRNP	ENST00000457586.2 linkuse as main transcript	c.351A>G	p.Ala117Ala	synonymous_variant	2/2	1		ENSP00000415284.2	P04156-1X6RKS3

Frequencies

GnomAD3 genomes

AF:

0.0418

AC:

6352

AN:

152142

Hom.:

193

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0840

Gnomad AMI

AF:

0.0385

Gnomad AMR

AF:

0.0228

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0316

Gnomad OTH

AF:

0.0368

GnomAD3 exomes

AF:

0.0253

AC:

6342

AN:

250404

Hom.:

131

AF XY:

0.0246

AC XY:

3328

AN XY:

135512

show subpopulations

Gnomad AFR exome

AF:

0.0870

Gnomad AMR exome

AF:

0.0175

Gnomad ASJ exome

AF:

0.0240

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0134

Gnomad FIN exome

AF:

0.00758

Gnomad NFE exome

AF:

0.0299

Gnomad OTH exome

AF:

0.0242

GnomAD4 exome

AF:

0.0299

AC:

43708

AN:

1461722

Hom.:

794

Cov.:

AF XY:

0.0295

AC XY:

21429

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0839

Gnomad4 AMR exome

AF:

0.0193

Gnomad4 ASJ exome

AF:

0.0242

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0144

Gnomad4 FIN exome

AF:

0.00774

Gnomad4 NFE exome

AF:

0.0321

Gnomad4 OTH exome

AF:

0.0303

GnomAD4 genome

AF:

0.0417

AC:

6351

AN:

152260

Hom.:

193

Cov.:

AF XY:

0.0399

AC XY:

2968

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0838

Gnomad4 AMR

AF:

0.0227

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0155

Gnomad4 FIN

AF:

0.00829

Gnomad4 NFE

AF:

0.0316

Gnomad4 OTH

AF:

0.0369

Alfa

AF:

0.0350

Hom.:

Bravo

AF:

0.0455

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0332

EpiControl

AF:

0.0337

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inherited prion disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.093

DANN

Benign

0.32

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