11-6617707-T-G

Variant names:

• chr11-6617707-T-G
• rs1800746
• NM_000391.4:c.299A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000391.4(TPP1):​c.299A>C​(p.Gln100Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q100R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TPP1 NM_000391.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• Publications: 10 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP1	NM_000391.4	MANE Select	c.299A>C	p.Gln100Pro	missense	Exon 4 of 13	NP_000382.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPP1	ENST00000299427.12	TSL:1 MANE Select	c.299A>C	p.Gln100Pro	missense	Exon 4 of 13	ENSP00000299427.6
	TPP1	ENST00000533371.6	TSL:1	c.-431A>C		5_prime_UTR	Exon 3 of 12	ENSP00000437066.1
	TPP1	ENST00000682424.1		c.185A>C	p.Gln62Pro	missense	Exon 3 of 12	ENSP00000507321.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251456 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.079
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.31
Sift	Benign	0.17	T
Sift4G	Benign	0.25	T
Polyphen		0.020	B
Vest4		0.51
MutPred		0.72		Loss of catalytic residue at Q100 (P = 0.0578)
MVP		0.75
MPC		0.28
ClinPred		0.29	T
GERP RS		5.7
Varity_R		0.86
gMVP		0.76
Mutation Taster		=60/40	polymorphism

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: rs1800746; hg19: chr11-6638938;