11-6617154-C-G

Variant names:

• chr11-6617154-C-G
• rs56144125
• NM_000391.4:c.509-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS1_Supporting

The NM_000391.4(TPP1):​c.509-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00126 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000538068: enzyme activity in the leukocytes and fibroblasts was very low to almost absent respectively (Sun Y et al., 2013)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: TPP1 NM_000391.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:38 O:2
• Conservation: PhyloP100: 4.61
• Publications: 51 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), Orphanet, G2P, Myriad Women’s Health, Genomics England PanelApp, PanelApp Australia
• autosomal recessive spinocerebellar ataxia 7

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000538068: enzyme activity in the leukocytes and fibroblasts was very low to almost absent respectively (Sun Y et al., 2013).; SCV000915544: "The variant results in a significant reduction in TPP1 protease activity to between 0 - 10% of wild type depending on the sample type (Sleat et al. 1999; Steinfeld et al. 2002; Miller et al. 2013)."; SCV002767822: RT-PCR studies showed intron 5 retention, resulting in p.(Val170Glyfs*29) which is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction) (PMID: 23418007).; SCV000262910: "In an assay testing TPP1 function, this variant showed a functionally abnormal result (Ma, 2021)."; SCV000696666: Enzyme activity in the in patients carrying this variant was very low to absent, suggesting it leads to loss of protein function (Sleat_1999).
• PP5: Variant 11-6617154-C-G is Pathogenic according to our data. Variant chr11-6617154-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00134 (1960/1461866) while in subpopulation NFE AF = 0.0017 (1895/1111994). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAdExome4. There are 927 alleles in the male GnomAdExome4 subpopulation. Median coverage is 41. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.509-1G>C		splice_acceptor intron	N/A	NP_000382.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP1	ENST00000299427.12	TSL:1 MANE Select	c.509-1G>C		splice_acceptor intron	N/A	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.-221-1G>C		splice_acceptor intron	N/A	ENSP00000437066.1	O14773-2
	TPP1	ENST00000895469.1		c.509-1G>C		splice_acceptor intron	N/A	ENSP00000565528.1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000941

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000402 AC: 101 AN: 251364 AF XY: 0.000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000836

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00134 AC: 1960 AN: 1461866 Hom.: 0 Cov.: 41 AF XY: 0.00127 AC XY: 927 AN XY: 727242

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00170 AC: 1895 AN: 1111994

Other (OTH) AF: 0.000795 AC: 48 AN: 60394

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74308

African (AFR) AF: 0.000217 AC: 9 AN: 41396

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000507 Hom.: 0

Bravo AF: 0.000484

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000600

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
19	-	-	Neuronal ceroid lipofuscinosis 2 (20)
12	-	-	not provided (12)
2	-	-	Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 (3)
2	-	-	Neuronal ceroid lipofuscinosis (2)
1	-	-	Autosomal recessive spinocerebellar ataxia 7 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	TPP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		4.6
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -41
DS_AL_spliceai		0.96		Position offset: -1

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

Other links and lift over

dbSNP: rs56144125; hg19: chr11-6638385; COSMIC: COSV99067420; COSMIC: COSV99067420;