rs200880556

Variant names:

• chr11-6614574-G-A
• NM_000391.4:c.1664C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-6614574-G-A
• chr11-6614574-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000391.4(TPP1):​c.1664C>T​(p.Ala555Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TPP1 NM_000391.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21990335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.1664C>T	p.Ala555Val	missense_variant	Exon 13 of 13	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12	c.1664C>T	p.Ala555Val	missense_variant	Exon 13 of 13	1	NM_000391.4	ENSP00000299427.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.82
DEOGEN2	Benign	0.31	T;.;.;.;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T;.;T;.;T;.;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.3	L;.;.;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N;N;.;.;.;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.20	T;T;.;.;.;.;.
Sift4G	Benign	0.29	T;T;.;.;.;.;.
Polyphen		0.029	B;.;.;.;.;.;.
Vest4		0.15
MutPred		0.39		Gain of ubiquitination at K558 (P = 0.0557);.;.;.;.;.;.;
MVP		0.88
MPC		0.19
ClinPred		0.19	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr11-6635805;