Genetic Variant PPT1:c.363-4G>A (chr1-40091403-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000310.4(PPT1):c.363-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,612,342 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 14 hom., cov: 31)

Exomes 𝑓: 0.0037 ( 92 hom. )

Consequence

PPT1
NM_000310.4 splice_region, intron

Scores

Splicing: ADA: 0.00003210

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.0210

Publications

8 publications found

Variant links:

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

PPT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-40091403-C-T is Benign according to our data. Variant chr1-40091403-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00398 (606/152178) while in subpopulation EAS AF = 0.0359 (186/5180). AF 95% confidence interval is 0.0317. There are 14 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PPT1	NM_000310.4	MANE Select	c.363-4G>A	splice_region intron	N/A	NP_000301.1
PPT1	NM_001363695.2		c.363-4G>A	splice_region intron	N/A	NP_001350624.1
PPT1	NM_001142604.2		c.125-1891G>A	intron	N/A	NP_001136076.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PPT1	ENST00000642050.2	MANE Select	c.363-4G>A	splice_region intron	N/A	ENSP00000493153.1
PPT1	ENST00000433473.8	TSL:1	c.360-4G>A	splice_region intron	N/A	ENSP00000394863.4
PPT1	ENST00000530704.6	TSL:1	n.363-4G>A	splice_region intron	N/A	ENSP00000431655.1

Frequencies

GnomAD3 genomes

AF:

0.00399

AC:

606

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0185

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0358

Gnomad SAS

AF:

0.00601

Gnomad FIN

AF:

0.000757

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.0103

AC:

2579

AN:

249792

AF XY:

0.00852

show subpopulations

Gnomad AFR exome

AF:

0.000868

Gnomad AMR exome

AF:

0.0483

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.0315

Gnomad FIN exome

AF:

0.000741

Gnomad NFE exome

AF:

0.000860

Gnomad OTH exome

AF:

0.00476

GnomAD4 exome

AF:

0.00370

AC:

5404

AN:

1460164

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

2565

AN XY:

726434

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33448

American (AMR)

AF:

0.0435

AC:

1943

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26122

East Asian (EAS)

AF:

0.0422

AC:

1673

AN:

39688

South Asian (SAS)

AF:

0.00620

AC:

534

AN:

86102

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000854

AC:

949

AN:

1110696

Other (OTH)

AF:

0.00331

AC:

200

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

276

552

829

1105

1381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00398

AC:

606

AN:

152178

Hom.:

Cov.:

AF XY:

0.00453

AC XY:

337

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41536

American (AMR)

AF:

0.0185

AC:

283

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.0359

AC:

186

AN:

5180

South Asian (SAS)

AF:

0.00581

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000757

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68006

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00277

Hom.:

Bravo

AF:

0.00612

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.000953

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Neuronal ceroid lipofuscinosis 1 (4)

not specified (3)

Central core myopathy (1)

Inborn genetic diseases (1)

PPT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.3

(source)

DANN

Benign

0.62

PhyloP100

-0.021

PromoterAI

-0.032

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0020

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over