11-6614669-A-T

Variant names:

• chr11-6614669-A-T
• rs1029334403
• NM_000391.4:c.1569T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000391.4(TPP1):​c.1569T>A​(p.His523Gln) 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. Synonymous variant affecting the same amino acid position (i.e. H523H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPP1 NM_000391.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Myriad Women’s Health, G2P, Orphanet
• autosomal recessive spinocerebellar ataxia 7

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285338 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.1569T>A	p.His523Gln	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.1569T>A	p.His523Gln	missense_variant	Exon 13 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	0.60
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T;.;T;.;T;.;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.
PhyloP100		1.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D;D;.;.;.;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0090	D;D;.;.;.;.;.
Sift4G	Benign	0.082	T;T;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.66
MutPred		0.61		Gain of disorder (P = 0.1492);.;.;.;.;.;.;
MVP		0.91
MPC		0.64
ClinPred		0.92	D
GERP RS		3.5
Varity_R		0.65
gMVP		0.85
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs1029334403; hg19: chr11-6635900;