rs1799990

Variant names:

• chr20-4699605-A-G
• rs1799990
• NM_000311.5:c.385A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000311.5(PRNP):​c.385A>G​(p.Met129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,613,794 control chromosomes in the GnomAD database, including 89,542 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (8515 hom., cov: 31)
  • Exomes 𝑓: 0.33 (81027 hom.)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:15 O:3
• Conservation: PhyloP100: 0.542
• Publications: 328 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000311.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0022065938).
• BP6: Variant 20-4699605-A-G is Benign according to our data. Variant chr20-4699605-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	NM_000311.5	MANE Select	c.385A>G	p.Met129Val	missense	Exon 2 of 2	NP_000302.1
	PRNP	NM_001080121.3		c.385A>G	p.Met129Val	missense	Exon 2 of 2	NP_001073590.1
	PRNP	NM_001080122.3		c.385A>G	p.Met129Val	missense	Exon 2 of 2	NP_001073591.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRNP	ENST00000379440.9	TSL:1 MANE Select	c.385A>G	p.Met129Val	missense	Exon 2 of 2	ENSP00000368752.4
	PRNP	ENST00000424424.2	TSL:1	c.385A>G	p.Met129Val	missense	Exon 2 of 2	ENSP00000411599.2
	PRNP	ENST00000430350.2	TSL:1	c.385A>G	p.Met129Val	missense	Exon 2 of 2	ENSP00000399376.2

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49966 AN: 151820 Hom.: 8501 Cov.: 31

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.0271

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.321

GnomAD2 exomes AF: 0.309 AC: 77663 AN: 251266 AF XY: 0.305

Gnomad AFR exome AF: 0.340

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.0241

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.328 AC: 479223 AN: 1461854 Hom.: 81027 Cov.: 71 AF XY: 0.325 AC XY: 236250 AN XY: 727218

African (AFR) AF: 0.336 AC: 11265 AN: 33480

American (AMR) AF: 0.409 AC: 18303 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 7225 AN: 26136

East Asian (EAS) AF: 0.0337 AC: 1339 AN: 39700

South Asian (SAS) AF: 0.258 AC: 22252 AN: 86256

European-Finnish (FIN) AF: 0.300 AC: 16007 AN: 53406

Middle Eastern (MID) AF: 0.308 AC: 1775 AN: 5768

European-Non Finnish (NFE) AF: 0.344 AC: 382114 AN: 1111992

Other (OTH) AF: 0.314 AC: 18943 AN: 60392

GnomAD4 genome AF: 0.329 AC: 50030 AN: 151940 Hom.: 8515 Cov.: 31 AF XY: 0.327 AC XY: 24291 AN XY: 74278

African (AFR) AF: 0.341 AC: 14110 AN: 41396

American (AMR) AF: 0.398 AC: 6076 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 955 AN: 3472

East Asian (EAS) AF: 0.0271 AC: 140 AN: 5162

South Asian (SAS) AF: 0.251 AC: 1209 AN: 4808

European-Finnish (FIN) AF: 0.313 AC: 3310 AN: 10574

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.340 AC: 23117 AN: 67936

Other (OTH) AF: 0.319 AC: 673 AN: 2112

Alfa AF: 0.332 Hom.: 28098

Bravo AF: 0.336

TwinsUK AF: 0.334 AC: 1240

ALSPAC AF: 0.353 AC: 1359

ESP6500AA AF: 0.341 AC: 1504

ESP6500EA AF: 0.336 AC: 2889

ExAC AF: 0.307 AC: 37316

Asia WGS AF: 0.187 AC: 654 AN: 3478

EpiCase AF: 0.331

EpiControl AF: 0.336

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Huntington disease-like 1 (2)
-	1	-	Autism spectrum disorder (1)
-	-	1	Fatal familial insomnia (1)
-	-	1	Gerstmann-Straussler-Scheinker syndrome;C0206042:Fatal familial insomnia;C0751254:Inherited Creutzfeldt-Jakob disease;C1847650:Spongiform encephalopathy with neuropsychiatric features;C1855588:Kuru, susceptibility to;C1864112:Huntington disease-like 1 (1)
-	-	1	Inherited Creutzfeldt-Jakob disease (1)
-	-	1	Inherited prion disease (1)
-	-	-	ALZHEIMER DISEASE, EARLY-ONSET, SUSCEPTIBILITY TO (1)
-	-	-	APHASIA, PRIMARY PROGRESSIVE, SUSCEPTIBILITY TO (1)
-	-	-	PRION DISEASE, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.54
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.024	D
Sift4G	Benign	0.28	T
Polyphen		0.082	B
Vest4		0.061
MPC		0.52
ClinPred		0.0031	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.78
Mutation Taster		=65/35	polymorphism (auto)

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: rs1799990; hg19: chr20-4680251; COSMIC: COSV65173587;