rs74315402

Variant names:

• chr20-4699570-C-T
• rs74315402
• NM_000311.5:c.350C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000311.5(PRNP):​c.350C>T​(p.Ala117Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A117A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.66

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRNP	NM_000311.5	c.350C>T	p.Ala117Val	missense_variant	Exon 2 of 2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9	c.350C>T	p.Ala117Val	missense_variant	Exon 2 of 2	1	NM_000311.5	ENSP00000368752.4
PRNP	ENST00000424424.2	c.350C>T	p.Ala117Val	missense_variant	Exon 2 of 2	1		ENSP00000411599.2
PRNP	ENST00000430350.2	c.350C>T	p.Ala117Val	missense_variant	Exon 2 of 2	1		ENSP00000399376.2
PRNP	ENST00000457586.2	c.350C>T	p.Ala117Val	missense_variant	Exon 2 of 2	1		ENSP00000415284.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 02, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the A117V variant forms proteolytic resistant fragments (Ctm-PrP) and causes cytotoxity and endocplasmic reticulum stress (PMID: 21298055, 24086135); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9707339, 19543376, 8614527, 24086135, 11385020, 29338055, 17494694, 23132868, 11087738, 25993001, 9285466, 2783132, 10506086, 7501157, 31413052, 10698707, 16246061, 32488064, 36975162, 35294616, 26791950, 21298055) -

Gerstmann-Straussler-Scheinker syndrome Pathogenic:1

Oct 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.66	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.9	M;M;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.84
MutPred		0.75		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		1.0
MPC		1.4
ClinPred		0.88	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.81

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: rs74315402; hg19: chr20-4680216;