rs7274758

chr20-4700664-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000311.5(PRNP):c.*682A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 178,038 control chromosomes in the GnomAD database, including 221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (217 hom., cov: 32)
  • Exomes 𝑓: 0.015 (4 hom.)
• Consequence: PRNP NM_000311.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0730

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-4700664-A-G is Benign according to our data. Variant chr20-4700664-A-G is described in ClinVar as [Benign]. Clinvar id is 338663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5	c.*682A>G		3_prime_UTR_variant	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.*682A>G		3_prime_UTR_variant	2/2	1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.*682A>G		3_prime_UTR_variant	2/2	1		P1
PRNP	ENST00000430350.2	c.*682A>G		3_prime_UTR_variant	2/2	1		P1
PRNP	ENST00000457586.2	c.*682A>G		3_prime_UTR_variant	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6599 AN: 152204 Hom.: 217 Cov.: 32

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0379

GnomAD4 exome AF: 0.0149 AC: 382 AN: 25716 Hom.: 4 Cov.: 0 AF XY: 0.0151 AC XY: 193 AN XY: 12780

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.0245

Gnomad4 ASJ exome AF: 0.0341

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.00741

Gnomad4 NFE exome AF: 0.0310

Gnomad4 OTH exome AF: 0.0218

GnomAD4 genome AF: 0.0433 AC: 6598 AN: 152322 Hom.: 217 Cov.: 32 AF XY: 0.0415 AC XY: 3092 AN XY: 74484

Gnomad4 AFR AF: 0.0895

Gnomad4 AMR AF: 0.0234

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0161

Gnomad4 FIN AF: 0.00828

Gnomad4 NFE AF: 0.0315

Gnomad4 OTH AF: 0.0380

Alfa AF: 0.0402 Hom.: 79

Bravo AF: 0.0474

Asia WGS AF: 0.0120 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2019

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.32
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs7274758; hg19: chr20-4681310;