chr11-6618780-T-C

Position:

chr11-6618780-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000391.4(TPP1):c.225A>G(p.Gln75=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

TPP1
NM_000391.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: -2.09

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-6618780-T-C is Pathogenic according to our data. Variant chr11-6618780-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553222.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=2}. Variant chr11-6618780-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-6618780-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4 linkuse as main transcript	c.225A>G	p.Gln75=	synonymous_variant	3/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12 linkuse as main transcript	c.225A>G	p.Gln75=	synonymous_variant	3/13	1	NM_000391.4	P1	O14773-1
	ENST00000545572.1 linkuse as main transcript			upstream_gene_variant		3

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

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251124

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135756

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neuronal ceroid lipofuscinosis, 2 (MIM#204500), and spinocerebellar ataxia, autosomal recessive 7 (MIM#609270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been functionally proven by RNA studies to cause the partial skipping of exon 3, resulting in a frameshift and the formation of a premature termination codon (p.(Tyr76Lysfs*10)). This transcript is predicted to undergo nonsense-mediated decay (NMD). There is some residual wildtype transcript, but this is at very low levels (<10%) (PMID: 34126256). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (8 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic and observed in individuals with neuronal ceroid lipofuscinosis (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, but more recently as likely pathogenic and pathogenic, in multiple compound heterozygous and homozygous individuals with neuronal ceroid lipofuscinosis (ClinVar, LOVD, PMID: 10330339; 31489614; 30771299; 32329550; 23418007; 32855042, Nunes, A. et al. (2020)). (SP) 0901 - This variant has strong evidence for segregation with disease (PMID: 23418007; 31489614). (SP) 1001 - 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)). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 08, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 28, 2020	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change affects codon 75 of the TPP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TPP1 protein. This variant is present in population databases (rs368709098, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 10330339, 23418007, 34126256). This variant is also known as 1946A>G. ClinVar contains an entry for this variant (Variation ID: 553222). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive spinocerebellar ataxia 7

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jul 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over