NM_000311.5:c.532G>T

Variant names:

• chr20-4699752-G-T
• rs74315403
• NM_000311.5:c.532G>T
• PRNP p.Asp178Tyr

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP3_Moderate

The NM_000311.5(PRNP):c.532G>T (p.Asp178Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,874 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.D178N: Pathogenic/Likely_pathogenic (ClinVar VariationId 39359, 2 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.94
• Publications: 418 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: Genomics England PanelApp, Ambry Genetics, 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 1 benign (OR vs. background: 8.3).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.D178N: Pathogenic/Likely_pathogenic (ClinVar VariationId 39359, 2 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PRNP NM_000311.5	MANE Select	c.532G>T p.Asp178Tyr	missense	Exon 2 of 2	Prot: NP_000302.1 UniProt:
	PRNP NM_001080121.3		c.532G>T p.Asp178Tyr	missense	Exon 2 of 2	Prot: NP_001073590.1 UniProt:
	PRNP NM_001080122.3		c.532G>T p.Asp178Tyr	missense	Exon 2 of 2	Prot: NP_001073591.1 UniProt:

PRNP NM_000311.5

MANE Select

HGVSc / HGVSpc.532G>Tp.Asp178Tyr

Exon rankExon 2 of 2

missense

Prot: NP_000302.1UniProt: P04156-1Q53YK7

PRNP NM_001080121.3

HGVSc / HGVSpc.532G>Tp.Asp178Tyr

Exon rankExon 2 of 2

missense

Prot: NP_001073590.1UniProt: Q53YK7P04156-1

PRNP NM_001080122.3

HGVSc / HGVSpc.532G>Tp.Asp178Tyr

Exon rankExon 2 of 2

missense

Prot: NP_001073591.1UniProt: Q53YK7P04156-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PRNP ENST00000379440.9	TSL:1MANE Select	c.532G>T p.Asp178Tyr	missense	Exon 2 of 2	Prot: ENSP00000368752.4 UniProt:
	PRNP ENST00000424424.2	TSL:1	c.532G>T p.Asp178Tyr	missense	Exon 2 of 2	Prot: ENSP00000411599.2 UniProt:
	PRNP ENST00000430350.2	TSL:1	c.532G>T p.Asp178Tyr	missense	Exon 2 of 2	Prot: ENSP00000399376.2 UniProt:

PRNP ENST00000379440.9

TSL:1MANE Select

HGVSc / HGVSpc.532G>Tp.Asp178Tyr

Exon rankExon 2 of 2

missense

Prot: ENSP00000368752.4UniProt: P04156

PRNP ENST00000424424.2

TSL:1

HGVSc / HGVSpc.532G>Tp.Asp178Tyr

Exon rankExon 2 of 2

missense

Prot: ENSP00000411599.2UniProt: P04156

PRNP ENST00000430350.2

TSL:1

HGVSc / HGVSpc.532G>Tp.Asp178Tyr

Exon rankExon 2 of 2

missense

Prot: ENSP00000399376.2UniProt: P04156

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461874	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.91	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-7.0
GPN-Star score	N/A	7.0
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.88	D
Mutation Taster	N/A	18/82	disease causing
MutationAssessor	Uncertain	2.9	M
PhyloP100	Uncertain	5.9
popEVE	Benign	-3.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.91
VESM-3B	Benign	-11

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs74315403;

hg19: chr20-4680398;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar