rs368709098

Variant names:

Variant summary

Our verdict is The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPP3_ModeratePP5_Strong

The NM_000391.4(TPP1):c.225A>G (p.Gln75Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000105 (AC=17) in the gnomAD database across 1,613,724 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000236. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002768068: "This variant has strong functional evidence supporting abnormal protein function. Individuals either compound heterozygous or homozygous for this variant, have been consistently demonstrated to have reduced Tpp1 enzyme activity, considered to be the gold standard of diagnosing individuals with neuronal ceroid lipofuscinosis 2 (PMID:10330339, PMID:32329550, PMID:23418007, Nunes, A. et al. (2020))."".

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

TPP1
NM_000391.4 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: -2.09

Publications

7 publications found

Variant links:

Genes affected

TPP1 (HGNC:2073): (tripeptidyl peptidase 1) This gene encodes a member of the sedolisin family of serine proteases. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates, and has weaker endopeptidase activity. It is synthesized as a catalytically-inactive enzyme which is activated and auto-proteolyzed upon acidification. Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis, which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome. [provided by RefSeq, Jul 2008]

TPP1 Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Natera, Myriad Women's Health, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
autosomal recessive spinocerebellar ataxia 7
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet

TPP1 links:

ENSG00000255680 (HGNC:):

ENSG00000255680 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000391.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 points.

PS3

Well-established functional study supports damaging effect (PS3); SCV002768068: "This variant has strong functional evidence supporting abnormal protein function. Individuals either compound heterozygous or homozygous for this variant, have been consistently demonstrated to have reduced Tpp1 enzyme activity, considered to be the gold standard of diagnosing individuals with neuronal ceroid lipofuscinosis 2 (PMID: 10330339, PMID: 32329550, PMID: 23418007, Nunes, A. et al. (2020))."

PM2

Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000236 — borderline rare for AR gene (base 0.001, raised to 0.00126 by highest known P/LP ClinVar AF 0.00126) — PM2 supporting.

PP3

Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.

PP5

ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000391.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP1	NM_000391.4	MANE Select	c.225A>G	p.Gln75Gln	synonymous	Exon 3 of 13	NP_000382.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPP1	ENST00000299427.12	TSL:1 MANE Select	c.225A>G	p.Gln75Gln	synonymous	Exon 3 of 13	ENSP00000299427.6	O14773-1
TPP1	ENST00000533371.6	TSL:1	c.-505A>G		5_prime_UTR	Exon 2 of 12	ENSP00000437066.1	O14773-2
TPP1	ENST00000528657.2	TSL:1	c.*412A>G		3_prime_UTR	Exon 2 of 2	ENSP00000435001.1	E9PME9

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251124

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53136

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

TOPMed (Bravo)

AF:

0.0000604

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.000165

AC:

AN:

42482

Hom.:

Local populations

ESP6500 (Exome Variant Server)

AF:

0.0000770

AC:

AN:

12994

show subpopulations

European American

AF:

0.00

AC:

AN:

8592

African American

AF:

0.000227

AC:

AN:

4402

Case/control cohorts

Cohort

Cases

Controls

Epi25

(Epilepsy)

1 / 41958AF: 0.0000238334

0 / 66888AF: 0

SCHEMA

(Schizophrenia)

1 / 113126AF: 0.00000883970

1 / 190618AF: 0.00000524609

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronal ceroid lipofuscinosis 2 (3)

not provided (3)

Autosomal recessive spinocerebellar ataxia 7 (1)

Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

-2.1

PromoterAI

0.0044

Neutral

(source)

AlphaGenome AVI

Pathogenic

(source)

GPN-Star LLR

-3.5

(source)

GPN-Star score

3.5

(source)

Mutation Taster

=99/1

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

3.0

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.97

Position offset: 1

DS_DL_spliceai

0.60

Position offset: -4

Pangolin (max)

Pathogenic

0.73

(source)

Pangolin gain

0.73

Position offset: 1

Pangolin loss

0.35

Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over