rs138744051

Positions:

chr11-6615455-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000391.4(TPP1):c.1253G>A(p.Arg418Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000839 in 1,614,188 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R418W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0042 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 3 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.164

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000391.4

BP4

Computational evidence support a benign effect (MetaRNN=0.011564642).

BP6

Variant 11-6615455-C-T is Benign according to our data. Variant chr11-6615455-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6615455-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00425 (647/152298) while in subpopulation AFR AF= 0.0146 (608/41572). AF 95% confidence interval is 0.0137. There are 3 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4 linkuse as main transcript	c.1253G>A	p.Arg418Gln	missense_variant	10/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12 linkuse as main transcript	c.1253G>A	p.Arg418Gln	missense_variant	10/13	1	NM_000391.4	P1	O14773-1

Frequencies

GnomAD3 genomes

AF:

0.00423

AC:

644

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00119

AC:

300

AN:

251452

Hom.:

AF XY:

0.000964

AC XY:

131

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000484

AC:

708

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000451

AC XY:

328

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0137

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00321

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.00425

AC:

647

AN:

152298

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

307

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0146

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00479

ESP6500AA

AF:

0.0159

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.00141

AC:

171

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 15, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TPP1: BP4, BS1, BS2 -

Neuronal ceroid lipofuscinosis 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 14, 2019	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 15, 2021

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.;.;.;.;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.88

D;.;D;.;D;.;D

MetaRNN

Benign

0.012

T;T;T;T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.72

N;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.66

N;N;.;.;.;.;.

REVEL

Benign

0.22

Sift

Benign

0.55

T;T;.;.;.;.;.

Sift4G

Benign

0.61

T;T;.;.;.;.;.

Polyphen

0.011

B;.;.;.;.;.;.

Vest4

0.18

MVP

0.76

MPC

0.22

ClinPred

0.0063

GERP RS

-0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.047

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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