rs762961919

Variant names:

• chr20-63931020-G-A
• rs762961919
• NM_025219.3:c.491G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-63931020-G-A
• chr20-63931020-G-C
• chr20-63931020-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_025219.3(DNAJC5):​c.491G>A​(p.Arg164Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000089 in 1,461,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: DNAJC5 NM_025219.3 missense, splice_region
• Scores: Splicing: ADA: 0.9573
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.75
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC5	NM_025219.3	c.491G>A	p.Arg164Lys	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000360864.9	NP_079495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC5	ENST00000360864.9	c.491G>A	p.Arg164Lys	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_025219.3	ENSP00000354111.4
DNAJC5	ENST00000470551.1	n.491G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 6	2		ENSP00000434744.1
DNAJC5	ENST00000703637.1	n.491G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 6			ENSP00000515413.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 249906 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461490 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727032

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

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111946

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000404 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Nov 07, 2013

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg164Lys (AGG>AAG): c.491 G>A in exon 4 of the DNAJC5 gene (NM_025219.2). The Arg164Lys missense change in the DNAJC5 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one positively charged amino acid for another at a position that is conserved in mammals but is not conserved in more distantly related species. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Arg164Lys is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Neuronal ceroid lipofuscinosis Uncertain:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 164 of the DNAJC5 protein (p.Arg164Lys). This variant is present in population databases (rs762961919, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DNAJC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 205376). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.24
Sift	Benign	0.42	T
Sift4G	Benign	0.59	T
Polyphen		0.0050	B
Vest4		0.30
MVP		0.85
MPC		0.82
ClinPred		0.12	T
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.59
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.76
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: rs762961919; hg19: chr20-62562373;