20-4699534-C-T

Variant names:

• chr20-4699534-C-T
• rs11538758
• NM_000311.5:c.314C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000311.5(PRNP):​c.314C>T​(p.Pro105Leu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P105T) has been classified 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: 2.24
• Publications: 95 publications found

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]

PRNP Gene-Disease associations (from GenCC):

• Gerstmann-Straussler-Scheinker syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• Huntington disease-like 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• inherited Creutzfeldt-Jakob disease

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• familial Alzheimer-like prion disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fatal familial insomnia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PrP systemic amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-4699533-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13413.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 20-4699534-C-T is Pathogenic according to our data. Variant chr20-4699534-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13404.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000311.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	NM_000311.5	MANE Select	c.314C>T	p.Pro105Leu	missense	Exon 2 of 2	NP_000302.1
	PRNP	NM_001080121.3		c.314C>T	p.Pro105Leu	missense	Exon 2 of 2	NP_001073590.1
	PRNP	NM_001080122.3		c.314C>T	p.Pro105Leu	missense	Exon 2 of 2	NP_001073591.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	ENST00000379440.9	TSL:1 MANE Select	c.314C>T	p.Pro105Leu	missense	Exon 2 of 2	ENSP00000368752.4
	PRNP	ENST00000424424.2	TSL:1	c.314C>T	p.Pro105Leu	missense	Exon 2 of 2	ENSP00000411599.2
	PRNP	ENST00000430350.2	TSL:1	c.314C>T	p.Pro105Leu	missense	Exon 2 of 2	ENSP00000399376.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Gerstmann-Straussler-Scheinker syndrome (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.87		Loss of glycosylation at P105 (P = 0.0092)
MVP		1.0
MPC		1.4
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.33
gMVP		0.85
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs11538758; hg19: chr20-4680180;