20-4699534-C-A

Position:

• chr20-4699534-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5 PP3_Moderate

The NM_000311.5(PRNP):​c.314C>A​(p.Pro105Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P105L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-4699534-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5	c.314C>A	p.Pro105Gln	missense_variant	2/2	ENST00000379440.9	NP_000302.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRNP	ENST00000379440.9	c.314C>A	p.Pro105Gln	missense_variant	2/2	1	NM_000311.5	ENSP00000368752	P1
PRNP	ENST00000424424.2	c.314C>A	p.Pro105Gln	missense_variant	2/2	1		ENSP00000411599	P1
PRNP	ENST00000430350.2	c.314C>A	p.Pro105Gln	missense_variant	2/2	1		ENSP00000399376	P1
PRNP	ENST00000457586.2	c.314C>A	p.Pro105Gln	missense_variant	2/2	1		ENSP00000415284	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;T;T;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;.;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.28
MutPred		0.73		Loss of glycosylation at P105 (P = 0.0092);Loss of glycosylation at P105 (P = 0.0092);Loss of glycosylation at P105 (P = 0.0092);Loss of glycosylation at P105 (P = 0.0092);
MVP		1.0
MPC		1.3
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.82

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: rs11538758; hg19: chr20-4680180; COSMIC: COSV65173628;