chr20-4686278-C-G

Variant names:

• chr20-4686278-C-G
• rs13040327
• ENST00000967833.1:c.-373C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000967833.1(PRNP):​c.-373C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0878 in 152,270 control chromosomes in the GnomAD database, including 874 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (873 hom., cov: 32)
  • Exomes 𝑓: 0.11 (1 hom.)
• Consequence: PRNP ENST00000967833.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.89
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Gerstmann-Straussler-Scheinker syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp
• Huntington disease-like 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• inherited Creutzfeldt-Jakob disease

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• familial Alzheimer-like prion disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fatal familial insomnia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PrP systemic amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 20-4686278-C-G is Benign according to our data. Variant chr20-4686278-C-G is described in ClinVar as Benign. ClinVar VariationId is 338639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000967833.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	NM_000311.5	MANE Select	c.-245C>G		upstream_gene	N/A	NP_000302.1	Q53YK7
	PRNP	NM_001080121.3		c.-240C>G		upstream_gene	N/A	NP_001073590.1	P04156-1
	PRNP	NM_001080122.3		c.-236C>G		upstream_gene	N/A	NP_001073591.1	P04156-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	ENST00000967833.1		c.-373C>G		5_prime_UTR	Exon 1 of 3	ENSP00000637892.1
	PRNP	ENST00000882184.1		c.-11+462C>G		intron	N/A	ENSP00000552243.1
	PRNP	ENST00000882185.1		c.-6+462C>G		intron	N/A	ENSP00000552244.1

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13366 AN: 152088 Hom.: 871 Cov.: 32

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0629

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.0857

GnomAD4 exome AF: 0.109 AC: 7 AN: 64 Hom.: 1 Cov.: 0 AF XY: 0.0962 AC XY: 5 AN XY: 52

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.125 AC: 7 AN: 56

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.0878 AC: 13367 AN: 152206 Hom.: 873 Cov.: 32 AF XY: 0.0870 AC XY: 6476 AN XY: 74396

African (AFR) AF: 0.0228 AC: 948 AN: 41556

American (AMR) AF: 0.0629 AC: 963 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0629 AC: 218 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4830

European-Finnish (FIN) AF: 0.187 AC: 1979 AN: 10588

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.130 AC: 8846 AN: 67980

Other (OTH) AF: 0.0848 AC: 179 AN: 2110

Alfa AF: 0.115 Hom.: 151

Bravo AF: 0.0758

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inherited prion disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		2.9
PromoterAI		-0.14	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13040327; hg19: chr20-4666924;