rs142672910

chr11-6614920-A-G

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.1497T>C(p.Pro499=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,614,116 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: TPP1 NM_000391.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.74

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=-0.52).
• BP6: Variant 11-6614920-A-G is Benign according to our data. Variant chr11-6614920-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 137706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00156 (238/152238) while in subpopulation AFR AF= 0.00525 (218/41528). AF 95% confidence interval is 0.00468. There are 2 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.1497T>C	p.Pro499=	synonymous_variant	12/13	ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.1497T>C	p.Pro499=	synonymous_variant	12/13	1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152122 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000310 AC: 78 AN: 251452 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135910

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000145 AC: 212 AN: 1461878 Hom.: 2 Cov.: 33 AF XY: 0.000127 AC XY: 92 AN XY: 727240

Gnomad4 AFR exome AF: 0.00502

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152238 Hom.: 2 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74434

Gnomad4 AFR AF: 0.00525

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00159

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	TPP1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2017

This alteration is classified as likely 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	-0.52
Cadd	Benign	11
Dann	Benign	0.85

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: rs142672910; hg19: chr11-6636151;