rs2555170

Variant names:

• chr11-6617368-T-C
• rs2555170
• NM_000391.4:c.441A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000391.4(TPP1):​c.441A>G​(p.Glu147Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00764 in 1,614,040 control chromosomes in the GnomAD database, including 769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (406 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (363 hom.)
• Consequence: TPP1 NM_000391.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0840
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-6617368-T-C is Benign according to our data. Variant chr11-6617368-T-C is described in ClinVar as Benign. ClinVar VariationId is 130610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.084 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 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.441A>G	p.Glu147Glu	synonymous	Exon 5 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.441A>G	p.Glu147Glu	synonymous	Exon 5 of 13	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.-289A>G		5_prime_UTR	Exon 4 of 12	ENSP00000437066.1	O14773-2
	TPP1	ENST00000895469.1		c.441A>G	p.Glu147Glu	synonymous	Exon 5 of 13	ENSP00000565528.1

Frequencies

GnomAD3 genomes AF: 0.0400 AC: 6080 AN: 152040 Hom.: 405 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0107 AC: 2688 AN: 251468 AF XY: 0.00791

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.00731

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00427 AC: 6240 AN: 1461884 Hom.: 363 Cov.: 34 AF XY: 0.00373 AC XY: 2712 AN XY: 727240

African (AFR) AF: 0.139 AC: 4663 AN: 33480

American (AMR) AF: 0.00836 AC: 374 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: 0.000359 AC: 31 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.0121 AC: 70 AN: 5768

European-Non Finnish (NFE) AF: 0.000337 AC: 375 AN: 1112004

Other (OTH) AF: 0.0106 AC: 643 AN: 60396

GnomAD4 genome AF: 0.0401 AC: 6097 AN: 152156 Hom.: 406 Cov.: 32 AF XY: 0.0388 AC XY: 2889 AN XY: 74396

African (AFR) AF: 0.138 AC: 5728 AN: 41464

American (AMR) AF: 0.0168 AC: 256 AN: 15282

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 67994

Other (OTH) AF: 0.0322 AC: 68 AN: 2112

Alfa AF: 0.0228 Hom.: 146

Bravo AF: 0.0463

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Neuronal ceroid lipofuscinosis 2 (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.2
DANN	Benign	0.78
PhyloP100		-0.084
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=294/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2555170; hg19: chr11-6638599;