rs146315473

Variant names:

• chr11-6617437-C-CA
• rs146315473
• NM_000391.4:c.381-10dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000391.4(TPP1):​c.381-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,614,016 control chromosomes in the GnomAD database, including 325 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.025 (159 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (166 hom.)
• Consequence: TPP1 NM_000391.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 2.55
• Publications: 0 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 11-6617437-C-CA is Benign according to our data. Variant chr11-6617437-C-CA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0851 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.381-10dupT		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.381-10dupT		intron	N/A	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.-349-10dupT		intron	N/A	ENSP00000437066.1	O14773-2
	TPP1	ENST00000895469.1		c.381-10dupT		intron	N/A	ENSP00000565528.1

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3854 AN: 152042 Hom.: 159 Cov.: 32

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.00689 AC: 1731 AN: 251316 AF XY: 0.00519

Gnomad AFR exome AF: 0.0898

Gnomad AMR exome AF: 0.00466

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00274 AC: 4011 AN: 1461856 Hom.: 166 Cov.: 34 AF XY: 0.00239 AC XY: 1741 AN XY: 727226

African (AFR) AF: 0.0896 AC: 2999 AN: 33476

American (AMR) AF: 0.00521 AC: 233 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00321 AC: 84 AN: 26136

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

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5764

European-Non Finnish (NFE) AF: 0.000244 AC: 271 AN: 1112002

Other (OTH) AF: 0.00631 AC: 381 AN: 60394

GnomAD4 genome AF: 0.0254 AC: 3869 AN: 152160 Hom.: 159 Cov.: 32 AF XY: 0.0244 AC XY: 1818 AN XY: 74394

African (AFR) AF: 0.0874 AC: 3626 AN: 41466

American (AMR) AF: 0.0109 AC: 167 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68014

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0102 Hom.: 11

Bravo AF: 0.0293

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
1	-	1	Neuronal ceroid lipofuscinosis 2 (2)
-	-	1	Neuronal ceroid lipofuscinosis (1)
-	-	1	Neuronal Ceroid-Lipofuscinosis, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
BranchPoint Hunter		5.0
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: rs146315473; hg19: chr11-6638668;