rs386833666

Variant names:

• chr1-40076891-C-A
• rs386833666
• NM_000310.4:c.749G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-40076891-C-A
• chr1-40076891-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000310.4(PPT1):​c.749G>T​(p.Gly250Val) 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G250D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPT1 NM_000310.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.16
• Publications: 7 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-40076891-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 861676.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 1-40076891-C-A is Pathogenic according to our data. Variant chr1-40076891-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56215.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPT1	NM_000310.4	c.749G>T	p.Gly250Val	missense_variant	Exon 8 of 9	ENST00000642050.2	NP_000301.1
PPT1	NM_001142604.2	c.440G>T	p.Gly147Val	missense_variant	Exon 5 of 6		NP_001136076.1
PPT1	NM_001363695.2	c.726+1669G>T		intron_variant	Intron 7 of 7		NP_001350624.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2	c.749G>T	p.Gly250Val	missense_variant	Exon 8 of 9		NM_000310.4	ENSP00000493153.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1 Pathogenic:1

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.
PhyloP100		6.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-8.0	.;.;D;.;.;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;.;D;.;.;D;.
Sift4G	Pathogenic	0.0010	.;.;D;.;.;T;.
Polyphen		1.0	D;.;.;.;.;D;.
Vest4		0.89, 0.83
MutPred		0.90		Loss of disorder (P = 0.0439);.;.;.;Loss of disorder (P = 0.0439);.;.;
MVP		0.99
MPC		0.65
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.69
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs386833666; hg19: chr1-40542563;