chr20-4699380-G-A

Position:

chr20-4699380-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000311.5(PRNP):c.160G>A(p.Gly54Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,611,090 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 5 hom. )

Consequence

PRNP
NM_000311.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.57

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=0.015181363).

BP6

Variant 20-4699380-G-A is Benign according to our data. Variant chr20-4699380-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 338646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699380-G-A is described in Lovd as [Pathogenic]. Variant chr20-4699380-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000204 (31/151648) while in subpopulation SAS AF= 0.00272 (13/4780). AF 95% confidence interval is 0.00161. There are 1 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5 linkuse as main transcript	c.160G>A	p.Gly54Ser	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.160G>A	p.Gly54Ser	missense_variant	2/2	1	NM_000311.5	ENSP00000368752	P1	P04156-1
PRNP	ENST00000424424.2 linkuse as main transcript	c.160G>A	p.Gly54Ser	missense_variant	2/2	1		ENSP00000411599	P1	P04156-1
PRNP	ENST00000430350.2 linkuse as main transcript	c.160G>A	p.Gly54Ser	missense_variant	2/2	1		ENSP00000399376	P1	P04156-1
PRNP	ENST00000457586.2 linkuse as main transcript	c.160G>A	p.Gly54Ser	missense_variant	2/2	1		ENSP00000415284	P1	P04156-1

Frequencies

GnomAD3 genomes

AF:

0.000205

AC:

AN:

151534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00272

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000650

AC:

161

AN:

247882

Hom.:

AF XY:

0.000830

AC XY:

112

AN XY:

134866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00431

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000233

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000432

AC:

630

AN:

1459442

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

419

AN XY:

725850

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000897

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00418

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000178

Gnomad4 OTH exome

AF:

0.000830

GnomAD4 genome

AF:

0.000204

AC:

AN:

151648

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000196

Gnomad4 SAS

AF:

0.00272

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.000652

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PRNP: BS1, BS2 -

Inherited prion disease

Benign:1

Likely 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Huntington disease-like 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

T;T;T;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.89

.;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Pathogenic

0.86

MutationTaster

Benign

0.85

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

0.12

B;B;.;.

Vest4

0.63

MVP

0.99

MPC

0.51

ClinPred

0.050

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.31

gMVP

0.42

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