rs766374425

Variant names:

• chr20-63931503-G-A
• rs766374425
• NM_025219.3:c.532G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_025219.3(DNAJC5):​c.532G>A​(p.Ala178Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,428,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: DNAJC5 NM_025219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.50
• Publications: 0 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30510157).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC5	NM_025219.3	c.532G>A	p.Ala178Thr	missense_variant	Exon 5 of 5	ENST00000360864.9	NP_079495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC5	ENST00000360864.9	c.532G>A	p.Ala178Thr	missense_variant	Exon 5 of 5	1	NM_025219.3	ENSP00000354111.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000980 AC: 2 AN: 204078 AF XY: 0.00000904

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: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1428352 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 2 AN XY: 708626

African (AFR) AF: 0.00 AC: 0 AN: 32678

American (AMR) AF: 0.00 AC: 0 AN: 41920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.00 AC: 0 AN: 38010

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1100510

Other (OTH) AF: 0.00 AC: 0 AN: 59342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000833 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:1

Oct 29, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs766374425, ExAC 0.006%). 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. This sequence change replaces alanine with threonine at codon 178 of the DNAJC5 protein (p.Ala178Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.30
Sift	Benign	0.16	T
Sift4G	Benign	0.23	T
Polyphen		0.34	B
Vest4		0.43
MVP		0.60
MPC		0.82
ClinPred		0.64	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.57
Mutation Taster		=63/37	polymorphism

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: rs766374425; hg19: chr20-62562856;