rs755445790

chr11-6616513-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP3 PP5 BS2

The NM_000391.4(TPP1):c.887-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,238,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TPP1 NM_000391.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9899
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: -0.208

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-6616513-T-C is Pathogenic according to our data. Variant chr11-6616513-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2649.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPP1	NM_000391.4	c.887-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000299427.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPP1	ENST00000299427.12	c.887-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000391.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 150980 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00147 AC: 173 AN: 117918 Hom.: 15 AF XY: 0.00167 AC XY: 109 AN XY: 65438

Gnomad AFR exome AF: 0.00214

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00123

Gnomad EAS exome AF: 0.00256

Gnomad SAS exome AF: 0.00198

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00320

GnomAD4 exome AF: 0.0000110 AC: 12 AN: 1087998 Hom.: 0 Cov.: 76 AF XY: 0.00000556 AC XY: 3 AN XY: 539600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000362

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000223

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 150980 Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1 AN XY: 73668

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	This sequence change falls in intron 7 of the TPP1 gene. It does not directly change the encoded amino acid sequence of the TPP1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with neuronal ceroid lipofuscinosis in a family and has also been observed in unrelated affected individuals (PMID: 17959406, 23266810). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS7-10A>G. ClinVar contains an entry for this variant (Variation ID: 2649). Studies have shown that this variant results in the activation of a cryptic splice site in intron 7 (PMID: 17959406). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	10
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.51		Position offset: -1
DS_AL_spliceai		0.51		Position offset: -10

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

Publications

LitVar

Other links and lift over

dbSNP: rs755445790; hg19: chr11-6637744;