rs386833626

Variant names:

• chr1-40097125-C-A
• rs386833626
• NM_000310.4:c.114G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-40097125-C-A
• chr1-40097125-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000310.4(PPT1):​c.114G>T​(p.Trp38Cys) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W38S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.48
• Publications: 4 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 9 ACMG points.

• PM1: In a hotspot region, there are 4 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 1-40097125-C-A is Pathogenic according to our data. Variant chr1-40097125-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56144.

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.114G>T	p.Trp38Cys	missense	Exon 1 of 9	NP_000301.1
	PPT1	NM_001363695.2		c.114G>T	p.Trp38Cys	missense	Exon 1 of 8	NP_001350624.1
	PPT1	NM_001142604.2		c.114G>T	p.Trp38Cys	missense	Exon 1 of 6	NP_001136076.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPT1	ENST00000642050.2	MANE Select	c.114G>T	p.Trp38Cys	missense	Exon 1 of 9	ENSP00000493153.1
	PPT1	ENST00000433473.8	TSL:1	c.114G>T	p.Trp38Cys	missense	Exon 1 of 9	ENSP00000394863.4
	PPT1	ENST00000530704.6	TSL:1	n.114G>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000431655.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Neuronal ceroid lipofuscinosis 1 (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.88		Loss of stability (P = 0.217)
MVP		0.94
MPC		0.73
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs386833626; hg19: chr1-40562797;