20-63930873-T-G

Variant names:

• chr20-63930873-T-G
• rs387907043
• NM_025219.3:c.344T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_025219.3(DNAJC5):​c.344T>G​(p.Leu115Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJC5 NM_025219.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.47
• Publications: 51 publications found

Genes affected

DNAJC5 (HGNC:16235): (DnaJ heat shock protein family (Hsp40) member C5) This gene is a member of the J protein family. J proteins function in many cellular processes by regulating the ATPase activity of 70 kDa heat shock proteins. The encoded protein plays a role in membrane trafficking and protein folding, and has been shown to have anti-neurodegenerative properties. The encoded protein is known to play a role in cystic fibrosis and Huntington's disease. A pseudogene of this gene is located on the short arm of chromosome 8. [provided by RefSeq, Nov 2010]

DNAJC5 Gene-Disease associations (from GenCC):

• ceroid lipofuscinosis, neuronal, 4 (Kufs type)

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• adult neuronal ceroid lipofuscinosis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 20-63930873-T-G is Pathogenic according to our data. Variant chr20-63930873-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025219.3. 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
	DNAJC5	NM_025219.3	MANE Select	c.344T>G	p.Leu115Arg	missense	Exon 4 of 5	NP_079495.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC5	ENST00000360864.9	TSL:1 MANE Select	c.344T>G	p.Leu115Arg	missense	Exon 4 of 5	ENSP00000354111.4
	DNAJC5	ENST00000470551.1	TSL:2	n.344T>G		non_coding_transcript_exon	Exon 4 of 6	ENSP00000434744.1
	DNAJC5	ENST00000703637.1		n.344T>G		non_coding_transcript_exon	Exon 4 of 6	ENSP00000515413.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000657 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ceroid lipofuscinosis, neuronal, 4 (Kufs type) Pathogenic:3

Research Unit for Rare Diseases, 1st Faculty of Medicine, Charles University in Prague

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.344T>G (p.(L115R)) in exon 4 of DNAJC5 (NM_025219.2) variant was reported by Noskova et al. in 2011 as causative for ausomal dominant adult-onset neuronal ceroid lipofuscinosis (DOI: 10.1016/j.ajhg.2011.07.003).

Jun 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 06, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21820099, 22073189). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.60 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030894 /PMID: 21820099). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21820099, 22073189, 22978711). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 22235333). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

not provided Pathogenic:1

Jun 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on protein function (Greaves et al., 2012; Jedlikov et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22978711, 26610600, 31919451, 24277206, 22235333, 21820099, 12112194, 11489285, 22073189, 22902780)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.028	D
Polyphen		0.069	B
Vest4		0.96
MutPred		0.63		Gain of solvent accessibility (P = 0.0039)
MVP		0.93
MPC		1.2
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.95
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs387907043; hg19: chr20-62562226;