rs1555274416

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006493.4(CLN5):​c.1074A>T​(p.Leu358Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

CLN5
NM_006493.4 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.255
Variant links:
Genes affected
CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]
FBXL3 (HGNC:13599): (F-box and leucine rich repeat protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15329257).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLN5NM_006493.4 linkc.1074A>T p.Leu358Phe missense_variant Exon 4 of 4 ENST00000377453.9 NP_006484.2 O75503A0A024R644
CLN5NM_001366624.2 linkc.*523A>T 3_prime_UTR_variant Exon 5 of 5 NP_001353553.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLN5ENST00000377453.9 linkc.1074A>T p.Leu358Phe missense_variant Exon 4 of 4 1 NM_006493.4 ENSP00000366673.5 O75503
ENSG00000283208ENST00000638147.2 linkc.565+4839A>T intron_variant Intron 3 of 4 5 ENSP00000490953.2 A0A1B0GWJ7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:1
Sep 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 527733). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 407 of the CLN5 protein (p.Leu407Phe). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
14
DANN
Uncertain
1.0
DEOGEN2
Benign
0.10
T;T
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.53
T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.0
.;L
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-2.7
.;D
REVEL
Benign
0.039
Sift
Benign
0.036
.;D
Polyphen
0.047
.;B
MutPred
0.26
.;Loss of stability (P = 0.158);
MVP
0.20
MPC
0.65
ClinPred
0.30
T
GERP RS
1.3
Varity_R
0.048

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555274416; hg19: chr13-77575101; API