chr11-6614875-T-A

Variant names:

• chr11-6614875-T-A
• rs1128396
• NM_000391.4:c.1542A>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000391.4(TPP1):​c.1542A>T​(p.Gly514Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,613,522 control chromosomes in the GnomAD database, including 25,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2976 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22593 hom.)
• Consequence: TPP1 NM_000391.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.208
• Publications: 21 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-6614875-T-A is Benign according to our data. Variant chr11-6614875-T-A is described in ClinVar as Benign. ClinVar VariationId is 130608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.208 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.341 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.1542A>T	p.Gly514Gly	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.1542A>T	p.Gly514Gly	synonymous	Exon 12 of 13	ENSP00000299427.6	O14773-1
	TPP1	ENST00000533371.6	TSL:1	c.813A>T	p.Gly271Gly	synonymous	Exon 11 of 12	ENSP00000437066.1	O14773-2
	TPP1	ENST00000895469.1		c.1539A>T	p.Gly513Gly	synonymous	Exon 12 of 13	ENSP00000565528.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29271 AN: 151578 Hom.: 2974 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.191 AC: 48076 AN: 251396 AF XY: 0.190

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.348

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.172 AC: 251162 AN: 1461826 Hom.: 22593 Cov.: 34 AF XY: 0.172 AC XY: 125290 AN XY: 727220

African (AFR) AF: 0.226 AC: 7564 AN: 33476

American (AMR) AF: 0.180 AC: 8035 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6194 AN: 26134

East Asian (EAS) AF: 0.341 AC: 13552 AN: 39700

South Asian (SAS) AF: 0.184 AC: 15850 AN: 86258

European-Finnish (FIN) AF: 0.140 AC: 7466 AN: 53398

Middle Eastern (MID) AF: 0.243 AC: 1404 AN: 5766

European-Non Finnish (NFE) AF: 0.161 AC: 179557 AN: 1111976

Other (OTH) AF: 0.191 AC: 11540 AN: 60394

GnomAD4 genome AF: 0.193 AC: 29306 AN: 151696 Hom.: 2976 Cov.: 32 AF XY: 0.193 AC XY: 14314 AN XY: 74136

African (AFR) AF: 0.219 AC: 9036 AN: 41330

American (AMR) AF: 0.210 AC: 3201 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 854 AN: 3460

East Asian (EAS) AF: 0.355 AC: 1826 AN: 5146

South Asian (SAS) AF: 0.198 AC: 949 AN: 4792

European-Finnish (FIN) AF: 0.136 AC: 1428 AN: 10526

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11355 AN: 67898

Other (OTH) AF: 0.202 AC: 424 AN: 2096

Alfa AF: 0.177 Hom.: 794

Bravo AF: 0.200

Asia WGS AF: 0.245 AC: 853 AN: 3478

EpiCase AF: 0.172

EpiControl AF: 0.173

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	Neuronal ceroid lipofuscinosis 2 (5)
-	-	3	not specified (3)
-	-	1	Autosomal recessive spinocerebellar ataxia 7 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.2
DANN	Benign	0.86
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1128396; hg19: chr11-6636106; COSMIC: COSV54990948; COSMIC: COSV54990948;