rs146315473

chr11-6617437-C-CA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000391.4(TPP1):c.381-10_381-9insT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,614,016 control chromosomes in the GnomAD database, including 325 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (159 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (166 hom.)
• Consequence: TPP1 NM_000391.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 2.55

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 -16 ACMG points.

• BP6: Variant 11-6617437-C-CA is Benign according to our data. Variant chr11-6617437-C-CA is described in ClinVar as [Likely_benign]. Clinvar id is 197664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.381-10_381-9insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.381-10_381-9insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3854 AN: 152042 Hom.: 159 Cov.: 32

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00689 AC: 1731 AN: 251316 Hom.: 63 AF XY: 0.00519 AC XY: 705 AN XY: 135852

Gnomad AFR exome AF: 0.0898

Gnomad AMR exome AF: 0.00466

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00274 AC: 4011 AN: 1461856 Hom.: 166 Cov.: 34 AF XY: 0.00239 AC XY: 1741 AN XY: 727226

Gnomad4 AFR exome AF: 0.0896

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.0254 AC: 3869 AN: 152160 Hom.: 159 Cov.: 32 AF XY: 0.0244 AC XY: 1818 AN XY: 74394

Gnomad4 AFR AF: 0.0874

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0102 Hom.: 11

Bravo AF: 0.0293

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2018	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 2022	Variant summary: TPP1 c.381-10dupT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0089 in 282666 control chromosomes, predominantly at a frequency of 0.089 within the African or African-American subpopulation in the gnomAD database, including 102 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 45 fold of the estimated maximal expected allele frequency for a pathogenic variant in TPP1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.381-10dupT in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (n=5), likely benign (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 03, 2014	- -

Neuronal ceroid lipofuscinosis 2 Pathogenic:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 05, 2018	The observed variant g.7024dupT was neither found in 1000 Genomes nor in ExAC databases. The in-silico prediction of the given variant is disease causing by MutationTaster2. -

Neuronal Ceroid-Lipofuscinosis, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs146315473; hg19: chr11-6638668;