rs1800753

Variant names:

• chr11-6615437-C-T
• rs1800753
• NM_000391.4:c.1266+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-6615437-C-T
• chr11-6615437-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000391.4(TPP1):​c.1266+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,614,182 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (91 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (78 hom.)
• Consequence: TPP1 NM_000391.4 splice_region, intron
• Scores: Splicing: ADA: 0.3776
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.142
• 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

ENSG00000285338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-6615437-C-T is Benign according to our data. Variant chr11-6615437-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.06 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.1266+5G>A		splice_region 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.1266+5G>A		splice_region intron	N/A	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.537+5G>A		splice_region intron	N/A	ENSP00000437066.1	O14773-2
	TPP1	ENST00000895469.1		c.1266+5G>A		splice_region intron	N/A	ENSP00000565528.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2715 AN: 152182 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.0620

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00479 AC: 1205 AN: 251436 AF XY: 0.00356

Gnomad AFR exome AF: 0.0626

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00194 AC: 2832 AN: 1461882 Hom.: 78 Cov.: 34 AF XY: 0.00172 AC XY: 1250 AN XY: 727246

African (AFR) AF: 0.0614 AC: 2055 AN: 33478

American (AMR) AF: 0.00371 AC: 166 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26136

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

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5768

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1112008

Other (OTH) AF: 0.00520 AC: 314 AN: 60396

GnomAD4 genome AF: 0.0179 AC: 2721 AN: 152300 Hom.: 91 Cov.: 32 AF XY: 0.0173 AC XY: 1285 AN XY: 74482

African (AFR) AF: 0.0620 AC: 2577 AN: 41548

American (AMR) AF: 0.00595 AC: 91 AN: 15304

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68022

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.00719 Hom.: 23

Bravo AF: 0.0209

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	5	not specified (5)
-	-	2	Neuronal ceroid lipofuscinosis 2 (2)
-	-	1	Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	16
DANN	Benign	0.69
PhyloP100		0.14
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
dbscSNV1_RF	Benign	0.31
SpliceAI score (max)		0.11		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: rs1800753; hg19: chr11-6636668; COSMIC: COSV54991391; COSMIC: COSV54991391;