NM_000391.4:c.225A>G

Variant names:

• chr11-6618780-T-C
• rs368709098
• NM_000391.4:c.225A>G
• TPP1 p.Gln75Gln

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: -2.09
• Publications: 5 publications found

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

ENSG00000255680 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		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))."
	PM2Absent/extremely low in population databases		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.
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.
	PP5Reputable source reports pathogenic		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	Prot: NP_000382.3

TPP1 NM_000391.4

MANE Select

HGVSc / HGVSpc.225A>Gp.Gln75Gln

Exon rankExon 3 of 13

synonymous

Prot: NP_000382.3

Ensembl Transcripts

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

TPP1 ENST00000299427.12

TSL:1MANE Select

HGVSc / HGVSpc.225A>Gp.Gln75Gln

Exon rankExon 3 of 13

synonymous

Prot: ENSP00000299427.6UniProt: O14773-1

TPP1 ENST00000533371.6

TSL:1

HGVSc / HGVSpc.-505A>G

Exon rankExon 2 of 12

5_prime_UTR

Prot: ENSP00000437066.1UniProt: O14773-2

TPP1 ENST00000528657.2

TSL:1

HGVSc / HGVSpc.*412A>G

Exon rankExon 2 of 2

3_prime_UTR

Prot: ENSP00000435001.1UniProt: E9PME9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000329	AC:5	Hom:0	AN:152124	Cov:32
GnomAD2 exomes	AF: 0.0000319	AC:8	Hom:	AN:251124	Cov:
GnomAD4 exome	AF: 0.00000821	AC:12	Hom:0	AN:1461600	Cov:31
GnomAD4 genome	AF: 0.0000329	AC:5	Hom:0	AN:152124	Cov:32
TOPMed (Bravo)	AF: 0.0000604	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000165	AC:7	Hom:0	AN:42482	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000770	AC:1	Hom:	AN:12994	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41958	0.00	0	66888
SCHEMA(Schizophrenia)	0.00000884	1	113126	0.00000525	1	190618

Showing 2 cohortsAllele 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

Pathogenic	VUS	Benign	Condition
2	1	-	Neuronal ceroid lipofuscinosis 2 (3)
3	-	-	not provided (3)
1	-	-	Autosomal recessive spinocerebellar ataxia 7 (1)
1	-	-	Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
BayesDel_noAF	Benign	-0.90
CADD	Benign	19
DANN	Benign	0.70
GPN-Star LLR	N/A	-3.5
GPN-Star score	N/A	3.5
Mutation Taster	N/A	99/1	disease causing (ClinVar)
PhyloP100	Benign	-2.1
PromoterAI	N/A	0.0044	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_DG_spliceai	Pathogenic	0.97	Position offset: 1
DS_DL_spliceai	Pathogenic	0.60	Position offset: -4
Pangolin (max)	Pathogenic	0.73
Pangolin gain	Pathogenic	0.73	Position offset: 1
Pangolin loss	Uncertain	0.35	Position offset: -4
SpliceAI score (max)	Pathogenic	0.97	Details are displayed if max score is > 0.2
Splicevardb	N/A	3.0

Showing 7 of 7 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs368709098;

hg19: chr11-6640011;

COSMIC: COSV54999847;

COSMIC: COSV54999847;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar