rs121908207

Variant names:

• chr11-6616718-C-T
• rs121908207
• NM_000391.4:c.829G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000391.4(TPP1):​c.829G>A​(p.Val277Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: TPP1 NM_000391.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 4.63

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]

ENSG00000285338 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 12) in uniprot entity TPP1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000391.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 11-6616718-C-T is Pathogenic according to our data. Variant chr11-6616718-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68749.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-6616718-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.829G>A	p.Val277Met	missense_variant	Exon 7 of 13	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12	c.829G>A	p.Val277Met	missense_variant	Exon 7 of 13	1	NM_000391.4	ENSP00000299427.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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

GnomAD4 exome Cov.: 41

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Pathogenic:1

Oct 28, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TPP1 c.829G>A (p.Val277Met) results in a conservative amino acid change located in the Sedolisin domain (IPR030400) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, structural studies predicted this variant as destabilization of alpha 8 and might affect active site (Pal_2009, Guhaniyogi_2009). The variant was absent in 251454 control chromosomes (gnomAD). c.829G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Ju_2002, Sleat_2016). These data indicate that the variant may be associated with disease. At least one functional study reports this variant showed no measurable TPPI activity (Walus_2010). Additionally, missense variants in nearby residues (L275P, D276V, Q278R, Q278Q) have been reported in the Human Gene Mutation Database in association with Neuronal ceroid lipofuscinosis, supporting the functional importance of this region of the protein. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Neuronal ceroid lipofuscinosis 2 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;.;D;.;D;.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N;N;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0050	D;D;.;.;.;.;.
Sift4G	Uncertain	0.013	D;D;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.89
MutPred		0.85		Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);.;.;
MVP		0.98
MPC		0.74
ClinPred		0.88	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.75

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: rs121908207; hg19: chr11-6637949;