Variant rs762961919 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. 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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC5	NM_025219.3 linkuse as main transcript	c.491G>A	p.Arg164Lys	missense_variant, splice_region_variant	4/5	ENST00000360864.9	NP_079495.1	Q9H3Z4-1Q6AHX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAJC5	ENST00000360864.9 linkuse as main transcript	c.491G>A	p.Arg164Lys	missense_variant, splice_region_variant	4/5	1	NM_025219.3	ENSP00000354111.4	Q9H3Z4-1
DNAJC5	ENST00000470551.1 linkuse as main transcript	n.491G>A		splice_region_variant, non_coding_transcript_exon_variant	4/6	2		ENSP00000434744.1	Q9H3Z4-2
DNAJC5	ENST00000703637.1 linkuse as main transcript	n.491G>A		splice_region_variant, non_coding_transcript_exon_variant	4/6			ENSP00000515413.1	Q9H3Z4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

249906

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135480

show subpopulations

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 SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461490

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727032

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:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000404

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2013

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DNAJC5-related disease. ClinVar contains an entry for this variant (Variation ID: 205376). This variant is present in population databases (rs762961919, ExAC 0.02%). This sequence change replaces arginine with lysine at codon 164 of the DNAJC5 protein (p.Arg164Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.76

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.19

REVEL

Benign

0.24

Sift

Benign

0.42

Sift4G

Benign

0.59

Polyphen

0.0050

Vest4

0.30

MVP

0.85

MPC

0.82

ClinPred

0.12

GERP RS

5.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.13

gMVP

0.59

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

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