rs386833744

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001042432.2(CLN3):c.988G>T(p.Val330Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,466 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V330I) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.31

Variant links:

Genes affected

CLN3 (HGNC:2074): (CLN3 lysosomal/endosomal transmembrane protein, battenin) This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

CLN3 links:

ENSG00000261832 (HGNC:):

ENSG00000261832 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a topological_domain Lumenal (size 47) in uniprot entity CLN3_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001042432.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-28482173-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 16-28482173-C-A is Pathogenic according to our data. Variant chr16-28482173-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28482173-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2 link	c.988G>T	p.Val330Phe	missense_variant	Exon 14 of 16	ENST00000636147.2	NP_001035897.1	Q13286-1A0A024QZB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2 link	c.988G>T	p.Val330Phe	missense_variant	Exon 14 of 16	1	NM_001042432.2	ENSP00000490105.1		Q13286-1
ENSG00000261832	ENST00000637378.1 link	c.160G>T	p.Val54Phe	missense_variant	Exon 4 of 10	5		ENSP00000490831.1		A0A1B0GW90

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461466

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3

Pathogenic:2

Feb 09, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Sep 11, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val330 amino acid residue in CLN3. Other variant(s) that disrupt this residue have been observed in individuals with CLN3-related conditions (PMID: 28542676), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects CLN3 protein function (PMID: 19132115). This variant has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9311735, 22013180). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56296). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 330 of the CLN3 protein (p.Val330Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

.;.;D;D;.;D;.;.;D;D;D;.;D;.;.;.;D

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;T;.;.;.;.;T;T;T;.;T;T;T;.;T;T;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;.;H;H;.;.;.;.;.;H;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.4

.;.;.;D;.;D;D;D;N;D;.;D;.;.;D;.;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

.;.;.;D;.;D;D;D;T;D;.;D;.;.;D;.;.

Sift4G

Pathogenic

0.0

.;.;.;.;.;D;D;D;.;D;.;D;.;.;.;.;.

Polyphen

1.0

.;.;D;D;.;D;.;.;.;D;D;D;D;.;D;.;.

Vest4

0.88, 0.89, 0.89, 0.88, 0.86

MutPred

0.92

.;.;Loss of MoRF binding (P = 0.1087);Loss of MoRF binding (P = 0.1087);.;.;.;.;.;Loss of MoRF binding (P = 0.1087);.;.;.;.;.;.;.;

MVP

0.97

MPC

0.73

ClinPred

1.0

GERP RS

5.4

Varity_R

0.97

gMVP

0.93

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over