1-40092494-G-GCAA

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 0 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: Likely_pathogenic. The variant received 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, 8 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 VariationId is 56180.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	NM_000310.4	MANE Select	c.135_137dupTTG	p.Cys46dup	disruptive_inframe_insertion	Exon 2 of 9	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	N/A	NP_001136076.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	ENST00000642050.2	MANE Select	c.135_137dupTTG	p.Cys46dup	disruptive_inframe_insertion	Exon 2 of 9	ENSP00000493153.1
	PPT1	ENST00000433473.8	TSL:1	c.132_134dupTTG	p.Cys45dup	disruptive_inframe_insertion	Exon 2 of 9	ENSP00000394863.4
	PPT1	ENST00000530704.6	TSL:1	n.135_137dupTTG		non_coding_transcript_exon	Exon 2 of 9	ENSP00000431655.1

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

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386833632; hg19: chr1-40558166;