TPP1 p.Phe378Leu

Variant names:

• chr11-6616016-G-T
• NM_000391.4:c.1134C>A
• TPP1 p.Phe378Leu

Your query was ambiguous. Multiple possible variants found:

• chr11-6616016-G-T
• chr11-6616016-G-C
• chr11-6616018-A-G
• chr11-6616016-GAA-AAG
• chr11-6616016-GAA-TAG
• chr11-6616016-GAA-CAG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000391.4(TPP1):​c.1134C>A​(p.Phe378Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPP1 NM_000391.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women's Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P
• autosomal recessive spinocerebellar ataxia 7

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet

ENSG00000285338 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000391.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP1	NM_000391.4	MANE Select	c.1134C>A	p.Phe378Leu	missense	Exon 9 of 13	NP_000382.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP1	ENST00000299427.12	TSL:1 MANE Select	c.1134C>A	p.Phe378Leu	missense	Exon 9 of 13	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.405C>A	p.Phe135Leu	missense	Exon 8 of 12	ENSP00000437066.1	O14773-2
	TPP1	ENST00000895469.1		c.1134C>A	p.Phe378Leu	missense	Exon 9 of 13	ENSP00000565528.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		1.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.015	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.75
gMVP		0.94
Mutation Taster		=44/56	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-6637247;