chr20-4699752-G-A

Position:

• chr20-4699752-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000311.5(PRNP):​c.532G>A​(p.Asp178Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRNP NM_000311.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 5.94

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 20-4699752-G-A is Pathogenic according to our data. Variant chr20-4699752-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-4699752-G-A is described in Lovd as [Pathogenic]. Variant chr20-4699752-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRNP	NM_000311.5	c.532G>A	p.Asp178Asn	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.532G>A	p.Asp178Asn	missense_variant	2/2	1	NM_000311.5	ENSP00000368752	P1
PRNP	ENST00000424424.2	c.532G>A	p.Asp178Asn	missense_variant	2/2	1		ENSP00000411599	P1
PRNP	ENST00000430350.2	c.532G>A	p.Asp178Asn	missense_variant	2/2	1		ENSP00000399376	P1
PRNP	ENST00000457586.2	c.532G>A	p.Asp178Asn	missense_variant	2/2	1		ENSP00000415284	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PRNP: PS3:Very Strong, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2023	Published functional studies demonstrate a damaging effect by accelerated misfolding and forming oligomers faster than wild-type protein (Singh et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32775516, 19996123, 1671440, 25959220, 16313190, 19571725, 10588836, 20872767, 25281825, 18062918, 10079068, 24118545, 23723004, 25473397, 20096809, 17494694, 14761942, 23132868, 9813003, 21689662, 23430483, 20038778, 21552571, 19543376, 22912570, 23276223, 19565837, 20104755, 15623717, 27056979, 26791950, 26074146, 17013786, 29569252, 9855529, 9270595, 9531435, 19228673, 29718878, 16227536, 10050890, 24340298, 32946318, 1439789, 8105681, 30012679, 10787305, 15459517, 33726816, 28549449) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Huntington disease-like 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039359, PMID:1671440, PS1_S). The variant was co-segregated with Gerstmann-Straussler disease in multiple affected family members with additional meioses (PMID: 10588836, 20038778) (PP1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9531435, 16227536, 26488179, 9270595, PS4_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 16313190, 23132868, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.731, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Gerstmann-Straussler disease (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 178 of the PRNP protein (p.Asp178Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with genetic prion diseases (PMID: 1439789, 1671440, 9270595, 9531435, 10588836, 16227536, 17013786, 20038778, 26488179, 26791950). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39359). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRNP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRNP function (PMID: 9813003, 16313190, 17494694, 23132868, 27350609). For these reasons, this variant has been classified as Pathogenic. -

Fatal familial insomnia Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
not provided, no classification provided	literature only	GeneReviews	-	Associated with Fatal Familial Insomnia phenotype; 1 of the 5 most common variants that account for 85% of genetic prion disease when in cis with Met129Val. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.9	M;M;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.96		Gain of MoRF binding (P = 0.1052);Gain of MoRF binding (P = 0.1052);Gain of MoRF binding (P = 0.1052);Gain of MoRF binding (P = 0.1052);
MVP		1.0
MPC		1.4
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.97

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: rs74315403; hg19: chr20-4680398;