13-76996035-G-C

Variant names:

• chr13-76996035-G-C
• rs386833978
• NM_006493.4:c.473G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_006493.4(CLN5):​c.473G>C​(p.Trp158Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W158R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0
• Publications: 5 publications found

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]

ENSG00000283208 (HGNC:):

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]

FBXL3 Gene-Disease associations (from GenCC):

• intellectual disability, short stature, facial anomalies, and joint dislocations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_006493.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 13-76996035-G-C is Pathogenic according to our data. Variant chr13-76996035-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56542.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006493.4. 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
	CLN5	NM_006493.4	MANE Select	c.473G>C	p.Trp158Ser	missense	Exon 3 of 4	NP_006484.2
	CLN5	NM_001366624.2		c.473G>C	p.Trp158Ser	missense	Exon 3 of 5	NP_001353553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.473G>C	p.Trp158Ser	missense	Exon 3 of 4	ENSP00000366673.5
	CLN5	ENST00000636183.2	TSL:1	c.473G>C	p.Trp158Ser	missense	Exon 3 of 4	ENSP00000490181.2
	ENSG00000283208	ENST00000638147.2	TSL:5	c.473G>C	p.Trp158Ser	missense	Exon 3 of 5	ENSP00000490953.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuronal ceroid lipofuscinosis 5 Pathogenic:1

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
REVEL	Pathogenic	0.80
Polyphen		1.0	D
MutPred		0.67		Gain of disorder (P = 0.0115)
MVP		1.0
MPC		0.94
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.026	Neutral
Varity_R		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs386833978; hg19: chr13-77570170;