1-40091361-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000310.4(PPT1):c.401T>C(p.Ile134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,613,744 control chromosomes in the GnomAD database, including 2,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I134S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.047 ( 303 hom., cov: 31)

Exomes 𝑓: 0.052 ( 2661 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.689

Publications

20 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: G2P, Myriad Women’s Health, Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

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 (MetaRNN=0.0022164583).

BP6

Variant 1-40091361-A-G is Benign according to our data. Variant chr1-40091361-A-G is described in ClinVar as Benign. ClinVar VariationId is 130022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
PPT1	NM_000310.4	MANE Select	c.401T>C	p.Ile134Thr	missense	Exon 4 of 9	NP_000301.1	P50897-1
PPT1	NM_001363695.2		c.401T>C	p.Ile134Thr	missense	Exon 4 of 8	NP_001350624.1	Q5T0S4
PPT1	NM_001142604.2		c.125-1849T>C		intron	N/A	NP_001136076.1	P50897-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPT1	ENST00000642050.2	MANE Select	c.401T>C	p.Ile134Thr	missense	Exon 4 of 9	ENSP00000493153.1	P50897-1
PPT1	ENST00000433473.8	TSL:1	c.398T>C	p.Ile133Thr	missense	Exon 4 of 9	ENSP00000394863.4	A0A2C9F2P4
PPT1	ENST00000530704.6	TSL:1	n.401T>C		non_coding_transcript_exon	Exon 4 of 9	ENSP00000431655.1	E9PK48

Frequencies

GnomAD3 genomes

AF:

0.0468

AC:

7115

AN:

152088

Hom.:

303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00961

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0351

Gnomad ASJ

AF:

0.0334

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0470

Gnomad OTH

AF:

0.0416

GnomAD2 exomes

AF:

0.0659

AC:

16560

AN:

251240

AF XY:

0.0698

show subpopulations

Gnomad AFR exome

AF:

0.00972

Gnomad AMR exome

AF:

0.0357

Gnomad ASJ exome

AF:

0.0316

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.0483

Gnomad OTH exome

AF:

0.0579

GnomAD4 exome

AF:

0.0523

AC:

76456

AN:

1461538

Hom.:

2661

Cov.:

AF XY:

0.0548

AC XY:

39880

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.00938

AC:

314

AN:

33480

American (AMR)

AF:

0.0355

AC:

1587

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0319

AC:

834

AN:

26134

East Asian (EAS)

AF:

0.125

AC:

4957

AN:

39696

South Asian (SAS)

AF:

0.118

AC:

10188

AN:

86226

European-Finnish (FIN)

AF:

0.130

AC:

6968

AN:

53404

Middle Eastern (MID)

AF:

0.0484

AC:

279

AN:

5768

European-Non Finnish (NFE)

AF:

0.0434

AC:

48253

AN:

1111722

Other (OTH)

AF:

0.0509

AC:

3076

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

3902

7804

11705

15607

19509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1842

3684

5526

7368

9210

<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:

0.0468

AC:

7117

AN:

152206

Hom.:

303

Cov.:

AF XY:

0.0535

AC XY:

3980

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00963

AC:

400

AN:

41552

American (AMR)

AF:

0.0351

AC:

536

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0334

AC:

116

AN:

3472

East Asian (EAS)

AF:

0.123

AC:

637

AN:

5182

South Asian (SAS)

AF:

0.127

AC:

612

AN:

4812

European-Finnish (FIN)

AF:

0.144

AC:

1523

AN:

10574

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0470

AC:

3195

AN:

68006

Other (OTH)

AF:

0.0412

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

331

661

992

1322

1653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0466

Hom.:

751

Bravo

AF:

0.0366

TwinsUK

AF:

0.0340

AC:

126

ALSPAC

AF:

0.0348

AC:

134

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.0474

AC:

408

ExAC

AF:

0.0661

AC:

8020

Asia WGS

AF:

0.122

AC:

421

AN:

3478

EpiCase

AF:

0.0447

EpiControl

AF:

0.0429

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Neuronal ceroid lipofuscinosis 1 (4)

not provided (3)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.62

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.4

PhyloP100

0.69

PrimateAI

Benign

0.44

REVEL

Benign

0.20

Polyphen

0.015

MPC

0.16

ClinPred

0.00074

GERP RS

2.4

PromoterAI

0.042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.093

gMVP

0.39

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

Publications

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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