rs35706972

Positions:

• chr11-6616346-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000391.4(TPP1):​c.1044C>T​(p.Ala348=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,516 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (8 hom., cov: 32)
  • Exomes 𝑓: 0.013 (150 hom.)
• Consequence: TPP1 NM_000391.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.51

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-6616346-G-A is Benign according to our data. Variant chr11-6616346-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00968 (1473/152232) while in subpopulation NFE AF= 0.0149 (1013/67992). AF 95% confidence interval is 0.0141. There are 8 homozygotes in gnomad4. There are 689 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.1044C>T	p.Ala348=	synonymous_variant	8/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.1044C>T	p.Ala348=	synonymous_variant	8/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.00970 AC: 1476 AN: 152114 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00994 AC: 2498 AN: 251370 Hom.: 17 AF XY: 0.0102 AC XY: 1390 AN XY: 135858

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00702

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.0128 AC: 18748 AN: 1461284 Hom.: 150 Cov.: 90 AF XY: 0.0125 AC XY: 9122 AN XY: 726978

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00631

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00658

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.00968 AC: 1473 AN: 152232 Hom.: 8 Cov.: 32 AF XY: 0.00926 AC XY: 689 AN XY: 74440

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0130 Hom.: 3

Bravo AF: 0.00859

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0126

EpiControl AF: 0.0127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 06, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TPP1: BP4, BP7, BS1, BS2 -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 15, 2017	- -

Neuronal ceroid lipofuscinosis 2 Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 21, 2021

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35706972; hg19: chr11-6637577;