rs6107516

Variant names:

• chr20-4696446-G-A
• rs6107516
• NM_000311.5:c.-10-2765G>A

Variant summary

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

The NM_000311.5(PRNP):​c.-10-2765G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,118 control chromosomes in the GnomAD database, including 4,095 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 0.23 (4095 hom., cov: 32)
• Consequence: PRNP NM_000311.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.669
• Publications: 29 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRNP	NM_000311.5	c.-10-2765G>A		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.-10-2765G>A		intron_variant	Intron 1 of 1	1	NM_000311.5	ENSP00000368752.4
PRNP	ENST00000424424.2	c.-5-2770G>A		intron_variant	Intron 1 of 1	1		ENSP00000411599.2
PRNP	ENST00000430350.2	c.-10-2765G>A		intron_variant	Intron 1 of 1	1		ENSP00000399376.2
PRNP	ENST00000457586.2	c.-10-2765G>A		intron_variant	Intron 1 of 1	1		ENSP00000415284.2

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34477 AN: 152000 Hom.: 4079 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.227 AC: 34552 AN: 152118 Hom.: 4095 Cov.: 32 AF XY: 0.223 AC XY: 16609 AN XY: 74374

African (AFR) AF: 0.209 AC: 8675 AN: 41496

American (AMR) AF: 0.284 AC: 4331 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 824 AN: 3468

East Asian (EAS) AF: 0.0204 AC: 106 AN: 5186

South Asian (SAS) AF: 0.176 AC: 851 AN: 4828

European-Finnish (FIN) AF: 0.210 AC: 2227 AN: 10580

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16739 AN: 67970

Other (OTH) AF: 0.237 AC: 501 AN: 2116

Alfa AF: 0.236 Hom.: 10361

Bravo AF: 0.232

Asia WGS AF: 0.133 AC: 462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.70
DANN	Benign	0.60
PhyloP100		-0.67
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: rs6107516; hg19: chr20-4677092;