rs72937434

Positions:

• chr1-40074145-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000310.4(PPT1):​c.837G>C​(p.Gln279His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,614,148 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (128 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (126 hom.)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.09

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 Benign. Variant got -18 ACMG points.

• PM1: In a chain Palmitoyl-protein thioesterase 1 (size 278) in uniprot entity PPT1_HUMAN there are 37 pathogenic changes around while only 3 benign (93%) in NM_000310.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0062122345).
• BP6: Variant 1-40074145-C-G is Benign according to our data. Variant chr1-40074145-C-G is described in ClinVar as [Benign]. Clinvar id is 130023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-40074145-C-G is described in Lovd as [Likely_benign]. Variant chr1-40074145-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.078 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT1	NM_000310.4	c.837G>C	p.Gln279His	missense_variant	9/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.765G>C	p.Gln255His	missense_variant	8/8		NP_001350624.1
PPT1	NM_001142604.2	c.528G>C	p.Gln176His	missense_variant	6/6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.837G>C	p.Gln279His	missense_variant	9/9		NM_000310.4	ENSP00000493153	P1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3480 AN: 152182 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00560 AC: 1409 AN: 251434 Hom.: 50 AF XY: 0.00426 AC XY: 579 AN XY: 135882

Gnomad AFR exome AF: 0.0789

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00237 AC: 3460 AN: 1461848 Hom.: 126 Cov.: 31 AF XY: 0.00201 AC XY: 1459 AN XY: 727224

Gnomad4 AFR exome AF: 0.0858

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.0229 AC: 3487 AN: 152300 Hom.: 128 Cov.: 32 AF XY: 0.0221 AC XY: 1648 AN XY: 74480

Gnomad4 AFR AF: 0.0803

Gnomad4 AMR AF: 0.00705

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00358 Hom.: 14

Bravo AF: 0.0263

ESP6500AA AF: 0.0731 AC: 322

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00676 AC: 821

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2020	Variant summary: PPT1 c.837G>C (p.Gln279His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0075 in 282822 control chromosomes, predominantly at a frequency of 0.079 within the African or African-American subpopulation in the gnomAD database, including 68 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 108 fold of the estimated maximal expected allele frequency for a pathogenic variant in PPT1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.00073), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.837G>C in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 30, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neuronal ceroid lipofuscinosis 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.;.;.;.
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D
MetaRNN	Benign	0.0062	T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.;.
MutationTaster	Benign	0.68	D;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	.;.;N;.;.;N;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	.;.;D;.;.;D;.
Sift4G	Uncertain	0.0040	.;.;D;.;.;D;.
Polyphen		0.69	P;.;.;.;.;P;.
Vest4		0.27, 0.22
MutPred		0.54		Gain of helix (P = 0.062);.;.;.;.;.;.;
MVP		0.95
MPC		0.42
ClinPred		0.016	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.54

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: rs72937434; hg19: chr1-40539817;