chr11-6612918-C-T

Position:

• chr11-6612918-C-T

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.*1628G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 152,654 control chromosomes in the GnomAD database, including 44,923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (44811 hom., cov: 32)
  • Exomes 𝑓: 0.69 (112 hom.)
• Consequence: TPP1 NM_000391.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.18

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=-0.78).
• BP6: Variant 11-6612918-C-T is Benign according to our data. Variant chr11-6612918-C-T is described in ClinVar as [Benign]. Clinvar id is 305489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.*1628G>A		3_prime_UTR_variant	13/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.*1628G>A		3_prime_UTR_variant	13/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.766 AC: 116461 AN: 152058 Hom.: 44764 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.873

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.805

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.746

Gnomad OTH AF: 0.774

GnomAD4 exome AF: 0.692 AC: 331 AN: 478 Hom.: 112 Cov.: 0 AF XY: 0.709 AC XY: 207 AN XY: 292

Gnomad4 FIN exome AF: 0.693

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.714

GnomAD4 genome AF: 0.766 AC: 116565 AN: 152176 Hom.: 44811 Cov.: 32 AF XY: 0.767 AC XY: 57054 AN XY: 74388

Gnomad4 AFR AF: 0.777

Gnomad4 AMR AF: 0.789

Gnomad4 ASJ AF: 0.805

Gnomad4 EAS AF: 0.894

Gnomad4 SAS AF: 0.784

Gnomad4 FIN AF: 0.719

Gnomad4 NFE AF: 0.746

Gnomad4 OTH AF: 0.776

Alfa AF: 0.756 Hom.: 44115

Bravo AF: 0.774

Asia WGS AF: 0.819 AC: 2847 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	-0.78
CADD	Benign	0.33
DANN	Benign	0.72
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: rs7488; hg19: chr11-6634149;