rs13045348

Variant names:

• chr20-4694943-T-C
• rs13045348
• NM_000311.5:c.-10-4268T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000311.5(PRNP):​c.-10-4268T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,002 control chromosomes in the GnomAD database, including 2,389 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2389 hom., cov: 31)
• Consequence: PRNP NM_000311.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.959
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRNP	NM_000311.5	c.-10-4268T>C		intron_variant	Intron 1 of 1	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9	c.-10-4268T>C		intron_variant	Intron 1 of 1	1	NM_000311.5	ENSP00000368752.4
PRNP	ENST00000424424.2	c.-5-4273T>C		intron_variant	Intron 1 of 1	1		ENSP00000411599.2
PRNP	ENST00000430350.2	c.-10-4268T>C		intron_variant	Intron 1 of 1	1		ENSP00000399376.2
PRNP	ENST00000457586.2	c.-10-4268T>C		intron_variant	Intron 1 of 1	1		ENSP00000415284.2

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24059 AN: 151884 Hom.: 2383 Cov.: 31

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.181

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 24071 AN: 152002 Hom.: 2389 Cov.: 31 AF XY: 0.156 AC XY: 11583 AN XY: 74292

African (AFR) AF: 0.0439 AC: 1821 AN: 41522

American (AMR) AF: 0.242 AC: 3688 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 809 AN: 3462

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5180

South Asian (SAS) AF: 0.167 AC: 805 AN: 4816

European-Finnish (FIN) AF: 0.162 AC: 1703 AN: 10508

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.213 AC: 14449 AN: 67956

Other (OTH) AF: 0.179 AC: 379 AN: 2112

Alfa AF: 0.206 Hom.: 2781

Bravo AF: 0.160

Asia WGS AF: 0.112 AC: 389 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.72
DANN	Benign	0.81
PhyloP100		-0.96
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: rs13045348; hg19: chr20-4675589;