20-4699190-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000311.5(PRNP):c.-10-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,612,998 control chromosomes in the GnomAD database, including 940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (183 hom., cov: 32)
  • Exomes 𝑓: 0.029 (757 hom.)
• Consequence: PRNP NM_000311.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.595

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 20-4699190-G-A is Benign according to our data. Variant chr20-4699190-G-A is described in ClinVar as [Benign]. Clinvar id is 1236587.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-4699190-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5	c.-10-21G>A		intron_variant		ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.-10-21G>A		intron_variant		1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.-5-26G>A		intron_variant		1		P1
PRNP	ENST00000430350.2	c.-10-21G>A		intron_variant		1		P1
PRNP	ENST00000457586.2	c.-10-21G>A		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.0409 AC: 6229 AN: 152144 Hom.: 183 Cov.: 32

Gnomad AFR AF: 0.0828

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00820

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0368

GnomAD3 exomes AF: 0.0245 AC: 6056 AN: 247646 Hom.: 124 AF XY: 0.0238 AC XY: 3202 AN XY: 134644

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0122

Gnomad FIN exome AF: 0.00749

Gnomad NFE exome AF: 0.0291

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0292 AC: 42657 AN: 1460736 Hom.: 757 Cov.: 31 AF XY: 0.0288 AC XY: 20896 AN XY: 726750

Gnomad4 AFR exome AF: 0.0830

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0242

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0128

Gnomad4 FIN exome AF: 0.00757

Gnomad4 NFE exome AF: 0.0314

Gnomad4 OTH exome AF: 0.0298

GnomAD4 genome AF: 0.0409 AC: 6228 AN: 152262 Hom.: 183 Cov.: 32 AF XY: 0.0389 AC XY: 2896 AN XY: 74450

Gnomad4 AFR AF: 0.0826

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.00820

Gnomad4 NFE AF: 0.0311

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0346 Hom.: 48

Bravo AF: 0.0449

Asia WGS AF: 0.0110 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.0050
Dann	Benign	0.56

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: rs78236631; hg19: chr20-4679836; COSMIC: COSV101057273;