11-6613428-C-G

Variant names:

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

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.*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. Variant has been reported in ClinVar as Benign (★★).

• 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: Orphanet, Myriad Women’s Health, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.93).
• BP6: Variant 11-6613428-C-G is Benign according to our data. Variant chr11-6613428-C-G is described in ClinVar as Benign. ClinVar VariationId is 305497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000391.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP1	NM_000391.4	MANE Select	c.*1118G>C		3_prime_UTR	Exon 13 of 13	NP_000382.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP1	ENST00000299427.12	TSL:1 MANE Select	c.*1118G>C		3_prime_UTR	Exon 13 of 13	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.*1118G>C		3_prime_UTR	Exon 12 of 12	ENSP00000437066.1	O14773-2
	TPP1	ENST00000895469.1		c.*1118G>C		3_prime_UTR	Exon 13 of 13	ENSP00000565528.1

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), 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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Neuronal ceroid lipofuscinosis 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;