11-6619387-G-T

Position:

• chr11-6619387-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000391.4(TPP1):​c.14C>A​(p.Ala5Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,190 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: TPP1 NM_000391.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: 0.237

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0105650425).
• BP6: Variant 11-6619387-G-T is Benign according to our data. Variant chr11-6619387-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92884.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=6}. Variant chr11-6619387-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPP1	NM_000391.4	c.14C>A	p.Ala5Asp	missense_variant	1/13	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12	c.14C>A	p.Ala5Asp	missense_variant	1/13	1	NM_000391.4	ENSP00000299427	P1
	ENST00000545572.1	n.87G>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00115 AC: 289 AN: 251492 Hom.: 0 AF XY: 0.00119 AC XY: 162 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00137 AC: 2001 AN: 1461886 Hom.: 2 Cov.: 31 AF XY: 0.00138 AC XY: 1002 AN XY: 727246

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00286

Gnomad4 NFE exome AF: 0.00154

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00121 AC: 185 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74480

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00188 Hom.: 0

Bravo AF: 0.000714

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00125 AC: 152

EpiCase AF: 0.000927

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2021	Has not been previously published as pathogenic or benign to our knowledge -

Neuronal ceroid lipofuscinosis 2 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 22, 2018	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2024	Variant summary: TPP1 c.14C>A (p.Ala5Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 1614190 control chromosomes in the gnomAD database, including 2 homozygotes. In addition, the allele frequency of this variant in Finnish population is slightly higher than the expected maximal pathogenic allele frequency of TPP1. c.14C>A has been reported in the literature in individuals affected with epilepsy (e.g., Al Anazi_2022). However, these report(s) do not provide unequivocal conclusions about association of the variant with TPP1-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36539902). ClinVar contains an entry for this variant (Variation ID: 92884). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 28, 2015	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

TPP1 NM_000391.3 exon 1 p.Ala5Asp (c.14C>A): This variant has not been reported in the literature but is present in 0.2% (70/25122) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-6640618-G-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:92884). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.38	T;.;.;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.63	T;T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.69	N;.;.;.;.
MutationTaster	Benign	0.94	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;.;.;.;D
REVEL	Uncertain	0.41
Sift	Benign	0.042	D;.;.;.;D
Sift4G	Benign	0.31	T;.;.;.;D
Polyphen		0.019	B;.;.;.;.
Vest4		0.70
MVP		0.62
MPC		0.29
ClinPred		0.029	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.39
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs138976576; hg19: chr11-6640618;