11-6612958-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000391.4(TPP1):c.*1588C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 152,556 control chromosomes in the GnomAD database, including 17,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (17523 hom., cov: 32)
  • Exomes 𝑓: 0.54 (66 hom.)
• Consequence: TPP1 NM_000391.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 11-6612958-G-A is Benign according to our data. Variant chr11-6612958-G-A is described in ClinVar as [Benign]. Clinvar id is 305490.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.*1588C>T		3_prime_UTR_variant	13/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.*1588C>T		3_prime_UTR_variant	13/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69413 AN: 151978 Hom.: 17518 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.682

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.481

GnomAD4 exome AF: 0.539 AC: 248 AN: 460 Hom.: 66 Cov.: 0 AF XY: 0.538 AC XY: 156 AN XY: 290

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.535

Gnomad4 NFE exome AF: 0.611

Gnomad4 OTH exome AF: 0.583

GnomAD4 genome AF: 0.456 AC: 69423 AN: 152096 Hom.: 17523 Cov.: 32 AF XY: 0.460 AC XY: 34232 AN XY: 74364

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.533

Gnomad4 ASJ AF: 0.522

Gnomad4 EAS AF: 0.530

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.540

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.485

Alfa AF: 0.529 Hom.: 10859

Bravo AF: 0.446

Asia WGS AF: 0.526 AC: 1828 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	13
Dann	Benign	0.75
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.2

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

LitVar

Other links and lift over

dbSNP: rs7487; hg19: chr11-6634189;