rs117942457

Variant names:

• chr11-6614923-G-A
• rs117942457
• NM_000391.4:c.1494C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-6614923-G-A
• chr11-6614923-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000391.4(TPP1):​c.1494C>T​(p.Pro498Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,108 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P498P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0087 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (132 hom.)
• Consequence: TPP1 NM_000391.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.03
• Publications: 5 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

ENSG00000285338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-6614923-G-A is Benign according to our data. Variant chr11-6614923-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00865 (1317/152226) while in subpopulation NFE AF = 0.0137 (931/68018). AF 95% confidence interval is 0.013. There are 6 homozygotes in GnomAd4. There are 638 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.1494C>T	p.Pro498Pro	synonymous	Exon 12 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.1494C>T	p.Pro498Pro	synonymous	Exon 12 of 13	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.765C>T	p.Pro255Pro	synonymous	Exon 11 of 12	ENSP00000437066.1	O14773-2
	TPP1	ENST00000895469.1		c.1491C>T	p.Pro497Pro	synonymous	Exon 12 of 13	ENSP00000565528.1

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1317 AN: 152108 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00863 AC: 2169 AN: 251474 AF XY: 0.00833

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00169

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.00879

GnomAD4 exome AF: 0.0118 AC: 17285 AN: 1461882 Hom.: 132 Cov.: 33 AF XY: 0.0113 AC XY: 8225 AN XY: 727246

African (AFR) AF: 0.00203 AC: 68 AN: 33480

American (AMR) AF: 0.00394 AC: 176 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.00161 AC: 64 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.0165 AC: 881 AN: 53410

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0139 AC: 15461 AN: 1112010

Other (OTH) AF: 0.00949 AC: 573 AN: 60396

GnomAD4 genome AF: 0.00865 AC: 1317 AN: 152226 Hom.: 6 Cov.: 32 AF XY: 0.00857 AC XY: 638 AN XY: 74436

African (AFR) AF: 0.00258 AC: 107 AN: 41526

American (AMR) AF: 0.00379 AC: 58 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.0190 AC: 201 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 931 AN: 68018

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00956 Hom.: 8

Bravo AF: 0.00727

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0115

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	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	-0.67
CADD	Benign	0.28
DANN	Benign	0.58
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117942457; hg19: chr11-6636154;