1-40097238-T-G

Variant names:

• chr1-40097238-T-G
• rs1085307087
• NM_000310.4:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PVS1 PS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_000310.4(PPT1):​c.1A>C​(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003239455: Studies have shown that disruption of the initiator codon alters PPT1 gene expression (PMID:11440996). Disruption of the initiator codon has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID:11440996).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPT1 NM_000310.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.12
• Publications: 1 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: G2P, Myriad Women’s Health, Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 24 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 25 pathogenic variants. Next in-frame start position is after 41 codons. Genomic position: 40097118. Lost 0.131 part of the original CDS.
• PS1: Another start lost variant in NM_000310.4 (PPT1) was described as [Likely_pathogenic] in ClinVar
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003239455: Studies have shown that disruption of the initiator codon alters PPT1 gene expression (PMID: 11440996). Disruption of the initiator codon has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 11440996).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-40097238-T-G is Pathogenic according to our data. Variant chr1-40097238-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2035352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	NM_000310.4	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	NP_000301.1	P50897-1
	PPT1	NM_001363695.2		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 8	NP_001350624.1	Q5T0S4
	PPT1	NM_001142604.2		c.1A>C	p.Met1?	initiator_codon	Exon 1 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.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000493153.1	P50897-1
	PPT1	ENST00000433473.8	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 9	ENSP00000394863.4	A0A2C9F2P4
	PPT1	ENST00000530704.6	TSL:1	n.1A>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000431655.1	E9PK48

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neuronal ceroid lipofuscinosis 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.042
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.61	D
PhyloP100		4.1
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.27	T
Polyphen		0.27	B
Vest4		0.95
MutPred		0.56		Loss of loop (P = 0.1242)
MVP		0.94
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		-0.97	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.48
Mutation Taster		=11/189	disease causing

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

Other links and lift over

dbSNP: rs1085307087; hg19: chr1-40562910;