11-6612958-G-A

Variant names:

• chr11-6612958-G-A
• rs7487
• NM_000391.4:c.*1588C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000391.4(TPP1):​c.*1588C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 152,556 control chromosomes in the GnomAD database, including 17,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17523 hom., cov: 32)
  • Exomes 𝑓: 0.54 (66 hom.)
• Consequence: TPP1 NM_000391.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08
• Publications: 15 publications found

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]

TPP1 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Myriad Women’s Health, G2P, Orphanet
• autosomal recessive spinocerebellar ataxia 7

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 11-6612958-G-A is Benign according to our data. Variant chr11-6612958-G-A is described in ClinVar as [Benign]. Clinvar id is 305490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.*1588C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000299427.12	NP_000382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPP1	ENST00000299427.12	c.*1588C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_000391.4	ENSP00000299427.6

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69413 AN: 151978 Hom.: 17518 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.682

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.481

GnomAD4 exome AF: 0.539 AC: 248 AN: 460 Hom.: 66 Cov.: 0 AF XY: 0.538 AC XY: 156 AN XY: 290

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.535 AC: 228 AN: 426

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.611 AC: 11 AN: 18

Other (OTH) AF: 0.583 AC: 7 AN: 12

GnomAD4 genome AF: 0.456 AC: 69423 AN: 152096 Hom.: 17523 Cov.: 32 AF XY: 0.460 AC XY: 34232 AN XY: 74364

African (AFR) AF: 0.222 AC: 9213 AN: 41482

American (AMR) AF: 0.533 AC: 8137 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1812 AN: 3470

East Asian (EAS) AF: 0.530 AC: 2737 AN: 5166

South Asian (SAS) AF: 0.520 AC: 2508 AN: 4824

European-Finnish (FIN) AF: 0.540 AC: 5713 AN: 10574

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37514 AN: 67984

Other (OTH) AF: 0.485 AC: 1025 AN: 2114

Alfa AF: 0.528 Hom.: 19713

Bravo AF: 0.446

Asia WGS AF: 0.526 AC: 1828 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neuronal ceroid lipofuscinosis 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.65
CADD	Benign	13
DANN	Benign	0.75
PhyloP100		1.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7487; hg19: chr11-6634189;