NM_000391.4:c.*1118G>C

Variant names:

• chr11-6613428-C-G
• rs1045450
• NM_000391.4:c.*1118G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000391.4(TPP1):​c.*1118G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 152,058 control chromosomes in the GnomAD database, including 7,777 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (7776 hom., cov: 32)
  • Exomes 𝑓: 0.38 (1 hom.)
• Consequence: TPP1 NM_000391.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.60
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPP1	NM_000391.4	c.*1118G>C		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.*1118G>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_000391.4	ENSP00000299427.6

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42558 AN: 151932 Hom.: 7740 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.375 AC: 3 AN: 8 Hom.: 1 Cov.: 0 AF XY: 0.750 AC XY: 3 AN XY: 4

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.281 AC: 42650 AN: 152050 Hom.: 7776 Cov.: 32 AF XY: 0.277 AC XY: 20627 AN XY: 74342

African (AFR) AF: 0.520 AC: 21556 AN: 41436

American (AMR) AF: 0.243 AC: 3720 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3468

East Asian (EAS) AF: 0.345 AC: 1784 AN: 5170

South Asian (SAS) AF: 0.219 AC: 1057 AN: 4826

European-Finnish (FIN) AF: 0.135 AC: 1426 AN: 10578

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.168 AC: 11432 AN: 67960

Other (OTH) AF: 0.273 AC: 577 AN: 2116

Alfa AF: 0.0914 Hom.: 120

Bravo AF: 0.301

Asia WGS AF: 0.277 AC: 966 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 12, 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	-0.93
CADD	Benign	0.63
DANN	Benign	0.19
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1045450; hg19: chr11-6634659;