rs386833632

Variant names:

• chr1-40092494-G-GCAA
• rs386833632
• NM_000310.4:c.135_137dupTTG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP3 PP5

The NM_000310.4(PPT1):​c.135_137dupTTG​(p.Cys46dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. C46C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPT1 NM_000310.4 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.55

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_pathogenic. Variant got 7 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, 6 uncertain in NM_000310.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000310.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-40092494-G-GCAA is Pathogenic according to our data. Variant chr1-40092494-G-GCAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56180.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPT1	NM_000310.4	c.135_137dupTTG	p.Cys46dup	disruptive_inframe_insertion	Exon 2 of 9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2	c.135_137dupTTG	p.Cys46dup	disruptive_inframe_insertion	Exon 2 of 8		NP_001350624.1
PPT1	NM_001142604.2	c.125-2985_125-2983dupTTG		intron_variant	Intron 1 of 5		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.135_137dupTTG	p.Cys46dup	disruptive_inframe_insertion	Exon 2 of 9		NM_000310.4	ENSP00000493153.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:1

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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386833632; hg19: chr1-40558166;