rs6037932

Variant names:

• chr20-4694509-A-T
• rs6037932
• NM_000311.5:c.-10-4702A>T

Variant summary

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

The NM_000311.5(PRNP):​c.-10-4702A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 152,074 control chromosomes in the GnomAD database, including 6,573 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 0.29 (6573 hom., cov: 32)
• Consequence: PRNP NM_000311.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.599
• Publications: 9 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.365 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.-10-4702A>T		intron	N/A	NP_000302.1
	PRNP	NM_001080121.3		c.-5-4707A>T		intron	N/A	NP_001073590.1
	PRNP	NM_001080122.3		c.-5-4707A>T		intron	N/A	NP_001073591.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	ENST00000379440.9	TSL:1 MANE Select	c.-10-4702A>T		intron	N/A	ENSP00000368752.4
	PRNP	ENST00000424424.2	TSL:1	c.-5-4707A>T		intron	N/A	ENSP00000411599.2
	PRNP	ENST00000430350.2	TSL:1	c.-10-4702A>T		intron	N/A	ENSP00000399376.2

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43599 AN: 151954 Hom.: 6558 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.287 AC: 43672 AN: 152074 Hom.: 6573 Cov.: 32 AF XY: 0.286 AC XY: 21256 AN XY: 74358

African (AFR) AF: 0.256 AC: 10603 AN: 41494

American (AMR) AF: 0.373 AC: 5702 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 858 AN: 3466

East Asian (EAS) AF: 0.0250 AC: 130 AN: 5196

South Asian (SAS) AF: 0.235 AC: 1135 AN: 4828

European-Finnish (FIN) AF: 0.296 AC: 3125 AN: 10556

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21131 AN: 67942

Other (OTH) AF: 0.282 AC: 594 AN: 2110

Alfa AF: 0.300 Hom.: 875

Bravo AF: 0.290

Asia WGS AF: 0.168 AC: 584 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.34
PhyloP100		-0.60
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: rs6037932; hg19: chr20-4675155;