1-40091361-A-G

Variant names:

• chr1-40091361-A-G
• rs1800205
• NM_000310.4:c.401T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000310.4(PPT1):​c.401T>C​(p.Ile134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,613,744 control chromosomes in the GnomAD database, including 2,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I134S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.047 (303 hom., cov: 31)
  • Exomes 𝑓: 0.052 (2661 hom.)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.689
• Publications: 20 publications found

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]

PPT1 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022164583).
• BP6: Variant 1-40091361-A-G is Benign according to our data. Variant chr1-40091361-A-G is described in ClinVar as Benign. ClinVar VariationId is 130022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000310.4. 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
	PPT1	NM_000310.4	MANE Select	c.401T>C	p.Ile134Thr	missense	Exon 4 of 9	NP_000301.1
	PPT1	NM_001363695.2		c.401T>C	p.Ile134Thr	missense	Exon 4 of 8	NP_001350624.1
	PPT1	NM_001142604.2		c.125-1849T>C		intron	N/A	NP_001136076.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	ENST00000642050.2	MANE Select	c.401T>C	p.Ile134Thr	missense	Exon 4 of 9	ENSP00000493153.1
	PPT1	ENST00000433473.8	TSL:1	c.398T>C	p.Ile133Thr	missense	Exon 4 of 9	ENSP00000394863.4
	PPT1	ENST00000530704.6	TSL:1	n.401T>C		non_coding_transcript_exon	Exon 4 of 9	ENSP00000431655.1

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 7115 AN: 152088 Hom.: 303 Cov.: 31

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0470

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0659 AC: 16560 AN: 251240 AF XY: 0.0698

Gnomad AFR exome AF: 0.00972

Gnomad AMR exome AF: 0.0357

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.0483

Gnomad OTH exome AF: 0.0579

GnomAD4 exome AF: 0.0523 AC: 76456 AN: 1461538 Hom.: 2661 Cov.: 32 AF XY: 0.0548 AC XY: 39880 AN XY: 727100

African (AFR) AF: 0.00938 AC: 314 AN: 33480

American (AMR) AF: 0.0355 AC: 1587 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 834 AN: 26134

East Asian (EAS) AF: 0.125 AC: 4957 AN: 39696

South Asian (SAS) AF: 0.118 AC: 10188 AN: 86226

European-Finnish (FIN) AF: 0.130 AC: 6968 AN: 53404

Middle Eastern (MID) AF: 0.0484 AC: 279 AN: 5768

European-Non Finnish (NFE) AF: 0.0434 AC: 48253 AN: 1111722

Other (OTH) AF: 0.0509 AC: 3076 AN: 60384

GnomAD4 genome AF: 0.0468 AC: 7117 AN: 152206 Hom.: 303 Cov.: 31 AF XY: 0.0535 AC XY: 3980 AN XY: 74412

African (AFR) AF: 0.00963 AC: 400 AN: 41552

American (AMR) AF: 0.0351 AC: 536 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3472

East Asian (EAS) AF: 0.123 AC: 637 AN: 5182

South Asian (SAS) AF: 0.127 AC: 612 AN: 4812

European-Finnish (FIN) AF: 0.144 AC: 1523 AN: 10574

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0470 AC: 3195 AN: 68006

Other (OTH) AF: 0.0412 AC: 87 AN: 2112

Alfa AF: 0.0466 Hom.: 751

Bravo AF: 0.0366

TwinsUK AF: 0.0340 AC: 126

ALSPAC AF: 0.0348 AC: 134

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.0474 AC: 408

ExAC AF: 0.0661 AC: 8020

Asia WGS AF: 0.122 AC: 421 AN: 3478

EpiCase AF: 0.0447

EpiControl AF: 0.0429

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Neuronal ceroid lipofuscinosis 1 Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Inborn genetic diseases Benign:1

Mar 17, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.69
PrimateAI	Benign	0.44	T
REVEL	Benign	0.20
Polyphen		0.015	B
MPC		0.16
ClinPred		0.00074	T
GERP RS		2.4
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.39
Mutation Taster		=93/7	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: rs1800205; hg19: chr1-40557033; COSMIC: COSV65655693;