rs119455954

Variant names:

• chr11-6616056-C-G
• NM_000391.4:c.1094G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-6616056-C-G
• chr11-6616056-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000391.4(TPP1):​c.1094G>C​(p.Cys365Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C365R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPP1 NM_000391.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.56

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-6616057-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.1094G>C	p.Cys365Ser	missense_variant	Exon 9 of 13	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12	c.1094G>C	p.Cys365Ser	missense_variant	Exon 9 of 13	1	NM_000391.4	ENSP00000299427.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;.;D;.;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.9	D;D;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0090	D;D;.;.;.;.;.
Sift4G	Uncertain	0.023	D;D;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.82
MutPred		0.78		Gain of disorder (P = 0.0013);.;.;.;.;.;.;
MVP		0.99
MPC		0.70
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-6637287;