chr1-40089495-G-A

Variant names:

• chr1-40089495-G-A
• rs137852700
• NM_000310.4:c.451C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000310.4(PPT1):​c.451C>T​(p.Arg151*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000454 in 1,613,878 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 (★★). ClinVar reports functional evidence for this variant: "SCV000242342: Published functional studies demonstrate the variant results in significantly decreased PPT1 levels (Miller et al., 2015)" and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: PPT1 NM_000310.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33 O:2
• Conservation: PhyloP100: 7.12
• Publications: 74 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: G2P, Myriad Women’s Health, Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000242342: Published functional studies demonstrate the variant results in significantly decreased PPT1 levels (Miller et al., 2015); SCV000357396: PPT1 enzyme activity levels are significantly reduced in NCL patients carrying the p.Arg151Ter variant when compared to controls (Mitchison et al. 1998; van Diggelen et al. 2001; Ramadan et al. 2007; Miller et al. 2013; Khan et al. 2013).; SCV004111860: This variant has been documented to be pathogenic for autosomal recessive neuronal ceroid lipofuscinoses (NCL), and its pathogenicity is supported by functional studies (Mitchison et al. 1998. PubMed ID: 9425237; Miller et al. 2013. PubMed ID: 23539563).
• PP5: Variant 1-40089495-G-A is Pathogenic according to our data. Variant chr1-40089495-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	NM_000310.4	MANE Select	c.451C>T	p.Arg151*	stop_gained	Exon 5 of 9	NP_000301.1	P50897-1
	PPT1	NM_001363695.2		c.451C>T	p.Arg151*	stop_gained	Exon 5 of 8	NP_001350624.1	Q5T0S4
	PPT1	NM_001142604.2		c.142C>T	p.Arg48*	stop_gained	Exon 2 of 6	NP_001136076.1	P50897-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	ENST00000642050.2	MANE Select	c.451C>T	p.Arg151*	stop_gained	Exon 5 of 9	ENSP00000493153.1	P50897-1
	PPT1	ENST00000433473.8	TSL:1	c.448C>T	p.Arg150*	stop_gained	Exon 5 of 9	ENSP00000394863.4	A0A2C9F2P4
	PPT1	ENST00000530704.6	TSL:1	n.*74C>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000431655.1	E9PK48

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152066 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000243 AC: 61 AN: 251412 AF XY: 0.000169

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000464 AC: 678 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.000433 AC XY: 315 AN XY: 727214

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000589 AC: 655 AN: 1111954

Other (OTH) AF: 0.000298 AC: 18 AN: 60390

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152066 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19 AN XY: 74272

African (AFR) AF: 0.0000966 AC: 4 AN: 41398

American (AMR) AF: 0.000131 AC: 2 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000488 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
19	-	-	Neuronal ceroid lipofuscinosis 1 (21)
9	-	-	not provided (9)
2	-	-	Neuronal ceroid lipofuscinosis (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neuronal Ceroid-Lipofuscinosis, Recessive (1)
1	-	-	PPT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.1
Vest4		0.84
GERP RS		5.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs137852700; hg19: chr1-40555167; COSMIC: COSV65655640; COSMIC: COSV65655640;