rs7274758

Variant names:

• chr20-4700664-A-G
• rs7274758
• NM_000311.5:c.*682A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 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: Ambry Genetics, Genomics England PanelApp, Orphanet
• Huntington disease-like 1

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.85).
• BP6: Variant 20-4700664-A-G is Benign according to our data. Variant chr20-4700664-A-G is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000311.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	NM_000311.5	MANE Select	c.*682A>G		3_prime_UTR	Exon 2 of 2	NP_000302.1
	PRNP	NM_001080121.3		c.*682A>G		3_prime_UTR	Exon 2 of 2	NP_001073590.1
	PRNP	NM_001080122.3		c.*682A>G		3_prime_UTR	Exon 2 of 2	NP_001073591.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	ENST00000379440.9	TSL:1 MANE Select	c.*682A>G		3_prime_UTR	Exon 2 of 2	ENSP00000368752.4
	PRNP	ENST00000424424.2	TSL:1	c.*682A>G		3_prime_UTR	Exon 2 of 2	ENSP00000411599.2
	PRNP	ENST00000430350.2	TSL:1	c.*682A>G		3_prime_UTR	Exon 2 of 2	ENSP00000399376.2

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

African (AFR) AF: 0.0270 AC: 2 AN: 74

American (AMR) AF: 0.0245 AC: 56 AN: 2286

Ashkenazi Jewish (ASJ) AF: 0.0341 AC: 3 AN: 88

East Asian (EAS) AF: 0.00 AC: 0 AN: 592

South Asian (SAS) AF: 0.0116 AC: 16 AN: 1378

European-Finnish (FIN) AF: 0.00741 AC: 110 AN: 14854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.0310 AC: 184 AN: 5932

Other (OTH) AF: 0.0218 AC: 11 AN: 504

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

African (AFR) AF: 0.0895 AC: 3718 AN: 41560

American (AMR) AF: 0.0234 AC: 358 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0161 AC: 78 AN: 4830

European-Finnish (FIN) AF: 0.00828 AC: 88 AN: 10628

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0315 AC: 2143 AN: 68030

Other (OTH) AF: 0.0380 AC: 80 AN: 2108

Alfa AF: 0.0419 Hom.: 87

Bravo AF: 0.0474

Asia WGS AF: 0.0120 AC: 45 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.85
CADD	Benign	0.32
DANN	Benign	0.72
PhyloP100		0.073
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs7274758; hg19: chr20-4681310;