rs121908195

Variant names:

• chr11-6618776-C-G
• rs121908195
• NM_000391.4:c.229G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-6618776-C-G
• chr11-6618776-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_000391.4(TPP1):​c.229G>C​(p.Gly77Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,454 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: "SCV000243405: in vitro functional studies indicate that this mutation impairs protein folding and significantly reduces TPP1 enzyme activity (Walus et al., 2010)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPP1 NM_000391.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.73
• Publications: 14 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

ENSG00000255680 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000243405: in vitro functional studies indicate that this mutation impairs protein folding and significantly reduces TPP1 enzyme activity (Walus et al., 2010).; SCV001576806: Experimental studies have shown that this missense change affects TPP1 function (PMID: 18411270, 20340139).; SCV001983463: Walus_2010 reported experimental evidence evaluating the protein level effect of the variant (i.e. expressing it from an intronless cDNA construct), and demonstrated very low residual enzyme activity and altered intracellular trafficking in a mammalian cell system. PMID:20172572
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-6618776-C-G is Pathogenic according to our data. Variant chr11-6618776-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 207567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.229G>C	p.Gly77Arg	missense splice_region	Exon 3 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.229G>C	p.Gly77Arg	missense splice_region	Exon 3 of 13	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.-501G>C		splice_region	Exon 2 of 12	ENSP00000437066.1	O14773-2
	TPP1	ENST00000533371.6	TSL:1	c.-501G>C		5_prime_UTR	Exon 2 of 12	ENSP00000437066.1	O14773-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250960 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461454 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727034

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52994

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Neuronal ceroid lipofuscinosis (1)
1	-	-	Neuronal ceroid lipofuscinosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.97		Loss of ubiquitination at K78 (P = 0.0566)
MVP		0.92
MPC		0.82
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.049	Neutral
Varity_R		0.91
gMVP		0.88
Mutation Taster		=196/104	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.80		Position offset: 0

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

Other links and lift over

dbSNP: rs121908195; hg19: chr11-6640007;