chr13-76995154-G-A

Variant names:

• chr13-76995154-G-A
• rs138110438
• NM_006493.4:c.265G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS1

The NM_006493.4(CLN5):​c.265G>A​(p.Asp89Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 1.35
• Publications: 1 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_benign. The variant received -6 ACMG points.

• PM1: In a disulfide_bond (size 89) in uniprot entity CLN5_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_006493.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.028666675).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000315 (48/152340) while in subpopulation AFR AF = 0.00106 (44/41570). AF 95% confidence interval is 0.00081. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.265G>A	p.Asp89Asn	missense	Exon 2 of 4	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.265G>A	p.Asp89Asn	missense	Exon 2 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.265G>A	p.Asp89Asn	missense	Exon 2 of 4	ENSP00000366673.5	O75503
	CLN5	ENST00000636183.2	TSL:1	c.265G>A	p.Asp89Asn	missense	Exon 2 of 4	ENSP00000490181.2	O75503
	ENSG00000283208	ENST00000638147.2	TSL:5	c.265G>A	p.Asp89Asn	missense	Exon 2 of 5	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251428 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000861

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: 0.0000287 AC: 42 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727208

African (AFR) AF: 0.00114 AC: 38 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111950

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74490

African (AFR) AF: 0.00106 AC: 44 AN: 41570

American (AMR) AF: 0.000196 AC: 3 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000306

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Neuronal ceroid lipofuscinosis 5 (3)
-	3	-	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.60	N
PhyloP100		1.4
PrimateAI	Benign	0.29	T
REVEL	Benign	0.084
Polyphen		0.0040	B
MVP		0.91
MPC		0.18
ClinPred		0.014	T
GERP RS		2.6
Varity_R		0.023
Mutation Taster		=99/1	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: rs138110438; hg19: chr13-77569289;