rs560471003

chr1-40089411-G-Achr1-40089411-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000310.4(PPT1):c.535C>T(p.Arg179Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000188 in 1,612,420 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (4 hom.)
• Consequence: PPT1 NM_000310.4 missense, splice_region
• Scores: Splicing: ADA: 0.001219
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 4.99

Genes affected

PPT1 (HGNC:9325): (palmitoyl-protein thioesterase 1) The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000310.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.034352362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPT1	NM_000310.4	c.535C>T	p.Arg179Cys	missense_variant, splice_region_variant	5/9	ENST00000642050.2
PPT1	NM_001363695.2	c.535C>T	p.Arg179Cys	missense_variant, splice_region_variant	5/8
PPT1	NM_001142604.2	c.226C>T	p.Arg76Cys	missense_variant, splice_region_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPT1	ENST00000642050.2	c.535C>T	p.Arg179Cys	missense_variant, splice_region_variant	5/9		NM_000310.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000922 AC: 14 AN: 151884 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000350 AC: 88 AN: 251414 Hom.: 1 AF XY: 0.000434 AC XY: 59 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1460420 Hom.: 4 Cov.: 32 AF XY: 0.000275 AC XY: 200 AN XY: 726628

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00262

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152000 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74256

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 30, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 14, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2020

The p.R179C variant (also known as c.535C>T), located in coding exon 5 of the PPT1 gene, results from a C to T substitution at nucleotide position 535. The arginine at codon 179 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2014

p.Arg179Cys (CGC>TGC): c.535 C>T in exon 5 of the PPT1 gene (NM_000310.3). The R179C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R179C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and Cysteine is observed at this position in evolution. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY,CHILD-EPI panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;.
Eigen	Benign	-0.067
Eigen_PC	Benign	0.018
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.034	T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.32	T
Polyphen		0.0040	B;.;.;.;.;B
Vest4		0.40
MutPred		0.73		Gain of catalytic residue at V181 (P = 0.087);.;.;Gain of catalytic residue at V181 (P = 0.087);Gain of catalytic residue at V181 (P = 0.087);.;
MVP		0.92
MPC		0.17
ClinPred		0.13	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.070		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: rs560471003; hg19: chr1-40555083;