rs140349036

Variant names:

• chr11-6616707-C-G
• rs140349036
• NM_000391.4:c.840G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000391.4(TPP1):​c.840G>C​(p.Leu280Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00355 in 1,614,094 control chromosomes in the GnomAD database, including 17 homozygotes. 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 0.0025 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (16 hom.)
• Consequence: TPP1 NM_000391.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 4.68
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-6616707-C-G is Benign according to our data. Variant chr11-6616707-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92885.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00253 (385/152240) while in subpopulation AMR AF = 0.00556 (85/15300). AF 95% confidence interval is 0.0046. There are 1 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 16 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.840G>C	p.Leu280Leu	synonymous	Exon 7 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.840G>C	p.Leu280Leu	synonymous	Exon 7 of 13	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.111G>C	p.Leu37Leu	synonymous	Exon 6 of 12	ENSP00000437066.1	O14773-2
	TPP1	ENST00000895469.1		c.840G>C	p.Leu280Leu	synonymous	Exon 7 of 13	ENSP00000565528.1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 152122 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00252 AC: 634 AN: 251452 AF XY: 0.00236

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00387

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00365 AC: 5337 AN: 1461854 Hom.: 16 Cov.: 41 AF XY: 0.00364 AC XY: 2649 AN XY: 727232

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.00297 AC: 133 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26136

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

South Asian (SAS) AF: 0.00187 AC: 161 AN: 86258

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53392

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00431 AC: 4793 AN: 1112002

Other (OTH) AF: 0.00290 AC: 175 AN: 60396

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152240 Hom.: 1 Cov.: 31 AF XY: 0.00232 AC XY: 173 AN XY: 74424

African (AFR) AF: 0.000650 AC: 27 AN: 41530

American (AMR) AF: 0.00556 AC: 85 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

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

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00372 AC: 253 AN: 68006

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00308 Hom.: 0

Bravo AF: 0.00274

EpiCase AF: 0.00354

EpiControl AF: 0.00338

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	2	not specified (3)
-	1	1	Neuronal ceroid lipofuscinosis 2 (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.0
DANN	Benign	0.85
PhyloP100		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs140349036; hg19: chr11-6637938;