rs386833638

Variant names:

• chr1-40092120-CACACTGTTGTTACTTG-AA
• rs386833638
• NM_000310.4:c.271_287delCAAGTAACAACAGTGTGinsTT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP3 PP5

The ENST00000642050.2(PPT1):​c.271_287delCAAGTAACAACAGTGTGinsTT​(p.Gln91_Cys96delinsPhe) variant causes a missense, conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPT1 ENST00000642050.2 missense, conservative_inframe_deletion
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.10
• 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 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000642050.2
• PM4: Nonframeshift variant in NON repetitive region in ENST00000642050.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-40092120-CACACTGTTGTTACTTG-AA is Pathogenic according to our data. Variant chr1-40092120-CACACTGTTGTTACTTG-AA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56186.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000642050.2. 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.271_287delCAAGTAACAACAGTGTGinsTT	p.Gln91_Cys96delinsPhe	missense conservative_inframe_deletion	N/A	NP_000301.1
	PPT1	NM_001363695.2		c.271_287delCAAGTAACAACAGTGTGinsTT	p.Gln91_Cys96delinsPhe	missense conservative_inframe_deletion	N/A	NP_001350624.1
	PPT1	NM_001142604.2		c.125-2624_125-2608delCAAGTAACAACAGTGTGinsTT		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.271_287delCAAGTAACAACAGTGTGinsTT	p.Gln91_Cys96delinsPhe	missense conservative_inframe_deletion	N/A	ENSP00000493153.1
	PPT1	ENST00000433473.8	TSL:1	c.268_284delCAAGTAACAACAGTGTGinsTT	p.Gln90_Cys95delinsPhe	missense conservative_inframe_deletion	N/A	ENSP00000394863.4
	PPT1	ENST00000530704.6	TSL:1	n.271_287delCAAGTAACAACAGTGTGinsTT		non_coding_transcript_exon	Exon 3 of 9	ENSP00000431655.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neuronal ceroid lipofuscinosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=6/194	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs386833638; hg19: chr1-40557792;