NM_006493.4:c.381T>G

Variant names:

• chr13-76995943-T-G
• rs34481987
• NM_006493.4:c.381T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006493.4(CLN5):​c.381T>G​(p.Thr127Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,614,110 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T127T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (34 hom., cov: 33)
  • Exomes 𝑓: 0.019 (418 hom.)
• Consequence: CLN5 NM_006493.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.284
• Publications: 8 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 13-76995943-T-G is Benign according to our data. Variant chr13-76995943-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.284 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

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.381T>G	p.Thr127Thr	synonymous	Exon 3 of 4	NP_006484.2
	CLN5	NM_001366624.2		c.381T>G	p.Thr127Thr	synonymous	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.381T>G	p.Thr127Thr	synonymous	Exon 3 of 4	ENSP00000366673.5
	CLN5	ENST00000636183.2	TSL:1	c.381T>G	p.Thr127Thr	synonymous	Exon 3 of 4	ENSP00000490181.2
	ENSG00000283208	ENST00000638147.2	TSL:5	c.381T>G	p.Thr127Thr	synonymous	Exon 3 of 5	ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2310 AN: 152200 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0702

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0202 AC: 5081 AN: 251484 AF XY: 0.0200

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.0274

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.0657

Gnomad FIN exome AF: 0.00651

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0190 AC: 27741 AN: 1461792 Hom.: 418 Cov.: 31 AF XY: 0.0186 AC XY: 13546 AN XY: 727210

African (AFR) AF: 0.00346 AC: 116 AN: 33480

American (AMR) AF: 0.0272 AC: 1216 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 347 AN: 26136

East Asian (EAS) AF: 0.0858 AC: 3408 AN: 39698

South Asian (SAS) AF: 0.0158 AC: 1360 AN: 86252

European-Finnish (FIN) AF: 0.00779 AC: 416 AN: 53420

Middle Eastern (MID) AF: 0.0253 AC: 146 AN: 5768

European-Non Finnish (NFE) AF: 0.0176 AC: 19552 AN: 1111924

Other (OTH) AF: 0.0195 AC: 1180 AN: 60390

GnomAD4 genome AF: 0.0152 AC: 2310 AN: 152318 Hom.: 34 Cov.: 33 AF XY: 0.0151 AC XY: 1128 AN XY: 74496

African (AFR) AF: 0.00397 AC: 165 AN: 41586

American (AMR) AF: 0.0241 AC: 369 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.0704 AC: 364 AN: 5170

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4826

European-Finnish (FIN) AF: 0.00555 AC: 59 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0164 AC: 1117 AN: 68030

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0176 Hom.: 70

Bravo AF: 0.0176

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.0179

EpiControl AF: 0.0193

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

May 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Neuronal ceroid lipofuscinosis 5 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Apr 14, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neuronal ceroid lipofuscinosis Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.7
DANN	Benign	0.74
PhyloP100		-0.28
PromoterAI		-0.0078	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs34481987; hg19: chr13-77570078; COSMIC: COSV66284714; COSMIC: COSV66284714;