rs1085307087

Positions:

• chr1-40097238-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000310.4(PPT1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,518 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: PPT1 NM_000310.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.12

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000310.4 (PPT1) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40097238-T-C is Pathogenic according to our data. Variant chr1-40097238-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225446.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT1	NM_000310.4	c.1A>G	p.Met1?	start_lost	1/9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.1A>G	p.Met1?	start_lost	1/8		NP_001350624.1
PPT1	NM_001142604.2	c.1A>G	p.Met1?	start_lost	1/6		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.1A>G	p.Met1?	start_lost	1/9		NM_000310.4	ENSP00000493153	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461518 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T;.;.;.;.;.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.52	.;.;N;.;.;N;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	.;.;D;.;.;D;D
Sift4G	Uncertain	0.030	.;.;D;.;.;D;.
Polyphen		0.46	P;.;.;.;.;P;.
Vest4		0.96, 0.96
MutPred		0.58		Gain of catalytic residue at M1 (P = 0.0128);Gain of catalytic residue at M1 (P = 0.0128);Gain of catalytic residue at M1 (P = 0.0128);Gain of catalytic residue at M1 (P = 0.0128);Gain of catalytic residue at M1 (P = 0.0128);Gain of catalytic residue at M1 (P = 0.0128);Gain of catalytic residue at M1 (P = 0.0128);
MVP		0.95
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.93
gMVP		0.60

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: rs1085307087; hg19: chr1-40562910;