rs2072651

Variant names:

• chr11-6616273-G-A
• rs2072651
• NM_000391.4:c.1075+42C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-6616273-G-A
• chr11-6616273-G-C
• chr11-6616273-G-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.1075+42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,611,728 control chromosomes in the GnomAD database, including 24,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2856 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22088 hom.)
• Consequence: TPP1 NM_000391.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.320

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]

ENSG00000285338 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-6616273-G-A is Benign according to our data. Variant chr11-6616273-G-A is described in ClinVar as [Benign]. Clinvar id is 670738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6616273-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.1075+42C>T		intron_variant	Intron 8 of 12	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12	c.1075+42C>T		intron_variant	Intron 8 of 12	1	NM_000391.4	ENSP00000299427.6

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28748 AN: 152034 Hom.: 2855 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.188 AC: 47001 AN: 249540 Hom.: 4733 AF XY: 0.187 AC XY: 25251 AN XY: 134988

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.334

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.170 AC: 248530 AN: 1459576 Hom.: 22088 Cov.: 31 AF XY: 0.171 AC XY: 123876 AN XY: 726184

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.237

Gnomad4 EAS exome AF: 0.332

Gnomad4 SAS exome AF: 0.175

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.189 AC: 28775 AN: 152152 Hom.: 2856 Cov.: 32 AF XY: 0.189 AC XY: 14059 AN XY: 74382

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.341

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.198

Alfa AF: 0.175 Hom.: 4476

Bravo AF: 0.196

Asia WGS AF: 0.236 AC: 822 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -

Autosomal recessive spinocerebellar ataxia 7 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.4
DANN	Benign	0.38

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: rs2072651; hg19: chr11-6637504; COSMIC: COSV54994523; COSMIC: COSV54994523;