rs34758634

Positions:

chr11-6617109-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000391.4(TPP1):c.553C>T(p.Arg185Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000548 in 1,614,148 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 4 hom., cov: 31)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

TPP1
NM_000391.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.70

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 -16 ACMG points.

BP6

Variant 11-6617109-G-A is Benign according to our data. Variant chr11-6617109-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 207577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6617109-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00303 (461/152282) while in subpopulation AFR AF= 0.0105 (435/41548). AF 95% confidence interval is 0.00966. There are 4 homozygotes in gnomad4. There are 207 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPP1	NM_000391.4 linkuse as main transcript	c.553C>T	p.Arg185Cys	missense_variant	6/13	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12 linkuse as main transcript	c.553C>T	p.Arg185Cys	missense_variant	6/13	1	NM_000391.4	ENSP00000299427	P1	O14773-1

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

460

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000867

AC:

218

AN:

251352

Hom.:

AF XY:

0.000611

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000290

AC:

424

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00956

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.00303

AC:

461

AN:

152282

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

207

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0105

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000579

Hom.:

Bravo

AF:

0.00332

ESP6500AA

AF:

0.0114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00114

AC:

138

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 19, 2016

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

This alteration is classified as likely 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. -

Neuronal ceroid lipofuscinosis 2

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;.

Eigen

Benign

0.053

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.2

N;.;.

REVEL

Benign

0.11

Sift

Uncertain

0.022

D;.;.

Sift4G

Uncertain

0.031

D;.;.

Polyphen

0.79

P;.;.

Vest4

0.39

MVP

0.74

MPC

0.49

ClinPred

0.033

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: -15

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