11-6616273-G-A

Variant names:

• chr11-6616273-G-A
• rs2072651
• NM_000391.4:c.1075+42C>T

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.1075+42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,611,728 control chromosomes in the GnomAD database, including 24,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2856 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22088 hom.)
• Consequence: TPP1 NM_000391.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.320
• Publications: 14 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), Genomics England PanelApp, Myriad Women’s Health, G2P, Orphanet
• autosomal recessive spinocerebellar ataxia 7

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285338 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-6616273-G-A is Benign according to our data. Variant chr11-6616273-G-A is described in ClinVar as Benign. ClinVar VariationId is 670738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 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.1075+42C>T		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.1075+42C>T		intron	N/A	ENSP00000299427.6
	TPP1	ENST00000533371.6	TSL:1	c.346+42C>T		intron	N/A	ENSP00000437066.1
	TPP1	ENST00000895469.1		c.1075+42C>T		intron	N/A	ENSP00000565528.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28748 AN: 152034 Hom.: 2855 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.188 AC: 47001 AN: 249540 AF XY: 0.187

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.334

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.170 AC: 248530 AN: 1459576 Hom.: 22088 Cov.: 31 AF XY: 0.171 AC XY: 123876 AN XY: 726184

African (AFR) AF: 0.215 AC: 7182 AN: 33440

American (AMR) AF: 0.178 AC: 7971 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6187 AN: 26130

East Asian (EAS) AF: 0.332 AC: 13178 AN: 39698

South Asian (SAS) AF: 0.175 AC: 15100 AN: 86172

European-Finnish (FIN) AF: 0.140 AC: 7442 AN: 53200

Middle Eastern (MID) AF: 0.231 AC: 1133 AN: 4898

European-Non Finnish (NFE) AF: 0.161 AC: 178977 AN: 1111070

Other (OTH) AF: 0.189 AC: 11360 AN: 60250

GnomAD4 genome AF: 0.189 AC: 28775 AN: 152152 Hom.: 2856 Cov.: 32 AF XY: 0.189 AC XY: 14059 AN XY: 74382

African (AFR) AF: 0.209 AC: 8656 AN: 41504

American (AMR) AF: 0.208 AC: 3183 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3472

East Asian (EAS) AF: 0.341 AC: 1762 AN: 5162

South Asian (SAS) AF: 0.189 AC: 913 AN: 4826

European-Finnish (FIN) AF: 0.135 AC: 1430 AN: 10604

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11324 AN: 67972

Other (OTH) AF: 0.198 AC: 419 AN: 2112

Alfa AF: 0.178 Hom.: 9384

Bravo AF: 0.196

Asia WGS AF: 0.236 AC: 822 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive spinocerebellar ataxia 7 (1)
-	-	1	Neuronal ceroid lipofuscinosis 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.4
DANN	Benign	0.38
PhyloP100		0.32
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: rs2072651; hg19: chr11-6637504; COSMIC: COSV54994523; COSMIC: COSV54994523;