13-77000567-G-C

Variant names:

• chr13-77000567-G-C
• rs1555274338
• NM_006493.4:c.675G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006493.4(CLN5):​c.675G>C​(p.Trp225Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	NM_006493.4	MANE Select	c.675G>C	p.Trp225Cys	missense	Exon 4 of 4	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.*124G>C		3_prime_UTR	Exon 5 of 5	NP_001353553.1	A0A1B0GTR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.675G>C	p.Trp225Cys	missense	Exon 4 of 4	ENSP00000366673.5	O75503
	CLN5	ENST00000636183.2	TSL:1	c.675G>C	p.Trp225Cys	missense	Exon 4 of 4	ENSP00000490181.2	O75503
	ENSG00000283208	ENST00000638147.2	TSL:5	c.565+4440G>C		intron	N/A	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251376 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727228

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		10
PrimateAI	Uncertain	0.66	T
REVEL	Pathogenic	0.86
Polyphen		0.77	P
MutPred		0.64		Loss of catalytic residue at W225 (P = 0.0057)
MVP		1.0
MPC		0.93
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.84
Mutation Taster		=16/84	disease causing

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: rs1555274338; hg19: chr13-77574702;