rs74315411

Positions:

• chr20-4699767-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000311.5(PRNP):​c.547A>G​(p.Thr183Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.54

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000311.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 20-4699767-A-G is Pathogenic according to our data. Variant chr20-4699767-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13407.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRNP	NM_000311.5	c.547A>G	p.Thr183Ala	missense_variant	2/2	ENST00000379440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRNP	ENST00000379440.9	c.547A>G	p.Thr183Ala	missense_variant	2/2	1	NM_000311.5	P1
PRNP	ENST00000424424.2	c.547A>G	p.Thr183Ala	missense_variant	2/2	1		P1
PRNP	ENST00000430350.2	c.547A>G	p.Thr183Ala	missense_variant	2/2	1		P1
PRNP	ENST00000457586.2	c.547A>G	p.Thr183Ala	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Huntington disease-like 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2023

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 183 of the PRNP protein (p.Thr183Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dementia (PMID: 9266722, 10631141, 15558291). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13407). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRNP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRNP function (PMID: 10079068, 23527023, 26713717, 33731477). For these reasons, this variant has been classified as Pathogenic. -

Spongiform encephalopathy with neuropsychiatric features Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;.;.
MutationTaster	Benign	0.99	A;A
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.95
MutPred		0.94		Loss of stability (P = 0.0897);Loss of stability (P = 0.0897);Loss of stability (P = 0.0897);Loss of stability (P = 0.0897);
MVP		1.0
MPC		1.4
ClinPred		0.96	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.97

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: rs74315411; hg19: chr20-4680413;