chr1-40080487-G-A

Variant names:

• chr1-40080487-G-A
• NM_000310.4:c.537C>T
• PPT1 p.Arg179Arg

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000310.4(PPT1):​c.537C>T​(p.Arg179Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPT1 NM_000310.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002235
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• 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: Orphanet, G2P, Myriad Women's Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.

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.537C>T	p.Arg179Arg	splice_region synonymous	Exon 6 of 9	NP_000301.1	P50897-1
	PPT1	NM_001363695.2		c.537C>T	p.Arg179Arg	splice_region synonymous	Exon 6 of 8	NP_001350624.1	Q5T0S4
	PPT1	NM_001142604.2		c.228C>T	p.Arg76Arg	splice_region synonymous	Exon 3 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.537C>T	p.Arg179Arg	splice_region synonymous	Exon 6 of 9	ENSP00000493153.1	P50897-1
	PPT1	ENST00000433473.8	TSL:1	c.534C>T	p.Arg178Arg	splice_region synonymous	Exon 6 of 9	ENSP00000394863.4	A0A2C9F2P4
	PPT1	ENST00000530704.6	TSL:1	n.*160C>T		splice_region non_coding_transcript_exon	Exon 6 of 9	ENSP00000431655.1	E9PK48

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.55
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.052
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-40546159;