11-6613428-C-G

Position:

• chr11-6613428-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000391.4(TPP1):​c.*1118G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 152,058 control chromosomes in the GnomAD database, including 7,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7776 hom., cov: 32)
  • Exomes 𝑓: 0.38 (1 hom.)
• Consequence: TPP1 NM_000391.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.60

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-6613428-C-G is Benign according to our data. Variant chr11-6613428-C-G is described in ClinVar as [Benign]. Clinvar id is 305497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6613428-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.*1118G>C		3_prime_UTR_variant	13/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.*1118G>C		3_prime_UTR_variant	13/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42558 AN: 151932 Hom.: 7740 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.375 AC: 3 AN: 8 Hom.: 1 Cov.: 0 AF XY: 0.750 AC XY: 3 AN XY: 4

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.281 AC: 42650 AN: 152050 Hom.: 7776 Cov.: 32 AF XY: 0.277 AC XY: 20627 AN XY: 74342

Gnomad4 AFR AF: 0.520

Gnomad4 AMR AF: 0.243

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.345

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.273

Alfa AF: 0.0914 Hom.: 120

Bravo AF: 0.301

Asia WGS AF: 0.277 AC: 966 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Neuronal ceroid lipofuscinosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.93
CADD	Benign	0.63
DANN	Benign	0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs1045450; hg19: chr11-6634659;