20-4699380-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_000311.5(PRNP):c.160G>A(p.Gly54Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,611,090 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.57

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015181363).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000204 (31/151648) while in subpopulation SAS AF= 0.00272 (13/4780). AF 95% confidence interval is 0.00161. There are 1 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5	c.160G>A	p.Gly54Ser	missense_variant	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.160G>A	p.Gly54Ser	missense_variant	2/2	1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.160G>A	p.Gly54Ser	missense_variant	2/2	1		P1
PRNP	ENST00000430350.2	c.160G>A	p.Gly54Ser	missense_variant	2/2	1		P1
PRNP	ENST00000457586.2	c.160G>A	p.Gly54Ser	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 31 AN: 151534 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00272

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000650 AC: 161 AN: 247882 Hom.: 1 AF XY: 0.000830 AC XY: 112 AN XY: 134866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000432 AC: 630 AN: 1459442 Hom.: 5 Cov.: 31 AF XY: 0.000577 AC XY: 419 AN XY: 725850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00418

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.000830

GnomAD4 genome AF: 0.000204 AC: 31 AN: 151648 Hom.: 1 Cov.: 32 AF XY: 0.000270 AC XY: 20 AN XY: 74134

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00272

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.000652 AC: 79

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inherited prion disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Huntington disease-like 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T;T;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	0.85	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.12	B;B;.;.
Vest4		0.63
MVP		0.99
MPC		0.51
ClinPred		0.050	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.31
gMVP		0.42

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: rs763524380; hg19: chr20-4680026;