rs78457562

Positions:

• chr20-63930841-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025219.3(DNAJC5):​c.322-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 1,612,042 control chromosomes in the GnomAD database, including 4,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (532 hom., cov: 33)
  • Exomes 𝑓: 0.072 (4431 hom.)
• Consequence: DNAJC5 NM_025219.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001350
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.529

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-63930841-C-T is Benign according to our data. Variant chr20-63930841-C-T is described in ClinVar as [Benign]. Clinvar id is 137124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63930841-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC5	NM_025219.3	c.322-10C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000360864.9	NP_079495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC5	ENST00000360864.9	c.322-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_025219.3	ENSP00000354111	P1
DNAJC5	ENST00000470551.1	c.322-10C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2		ENSP00000434744
DNAJC5	ENST00000703637.1	c.322-10C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant				ENSP00000515413

Frequencies

GnomAD3 genomes AF: 0.0744 AC: 11319 AN: 152200 Hom.: 528 Cov.: 33

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.0343

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.0651

GnomAD3 exomes AF: 0.0654 AC: 16368 AN: 250390 Hom.: 783 AF XY: 0.0641 AC XY: 8686 AN XY: 135478

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.0432

Gnomad EAS exome AF: 0.00180

Gnomad SAS exome AF: 0.0413

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.0731

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0723 AC: 105498 AN: 1459724 Hom.: 4431 Cov.: 32 AF XY: 0.0714 AC XY: 51875 AN XY: 726160

Gnomad4 AFR exome AF: 0.0705

Gnomad4 AMR exome AF: 0.0320

Gnomad4 ASJ exome AF: 0.0445

Gnomad4 EAS exome AF: 0.00242

Gnomad4 SAS exome AF: 0.0408

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.0751

Gnomad4 OTH exome AF: 0.0681

GnomAD4 genome AF: 0.0745 AC: 11344 AN: 152318 Hom.: 532 Cov.: 33 AF XY: 0.0775 AC XY: 5770 AN XY: 74478

Gnomad4 AFR AF: 0.0685

Gnomad4 AMR AF: 0.0470

Gnomad4 ASJ AF: 0.0464

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.0340

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.0792

Gnomad4 OTH AF: 0.0653

Alfa AF: 0.0751 Hom.: 137

Bravo AF: 0.0635

Asia WGS AF: 0.0370 AC: 129 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ceroid lipofuscinosis, neuronal, 4 (Kufs type) Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuronal ceroid lipofuscinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Neuronal Ceroid-Lipofuscinosis, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.63
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs78457562; hg19: chr20-62562194;