3-132447458-T-G

Position:

• chr3-132447458-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The ENST00000260818.11(DNAJC13):​c.282T>G​(p.Leu94=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,574,692 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (18 hom., cov: 32)
  • Exomes 𝑓: 0.016 (208 hom.)
• Consequence: DNAJC13 ENST00000260818.11 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 1.24

Genes affected

DNAJC13 (HGNC:30343): (DnaJ heat shock protein family (Hsp40) member C13) This gene encodes a member of the Dnaj protein family whose members act as co-chaperones of a partner heat-shock protein by binding to the latter and stimulating ATP hydrolysis. The encoded protein associates with the heat-shock protein Hsc70 and plays a role in clathrin-mediated endocytosis. It may also be involved in post-endocytic transport mechanisms via its associations with other proteins, including the sorting nexin SNX1. Mutations in this gene are associated with Parkinson's disease. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 3-132447458-T-G is Benign according to our data. Variant chr3-132447458-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1210070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-132447458-T-G is described in Lovd as [Likely_benign]. Variant chr3-132447458-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1738/152224) while in subpopulation NFE AF= 0.0167 (1136/67976). AF 95% confidence interval is 0.0159. There are 18 homozygotes in gnomad4. There are 842 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1738 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC13	NM_015268.4	c.282T>G	p.Leu94=	synonymous_variant	4/56	ENST00000260818.11	NP_056083.3
DNAJC13	NM_001329126.2	c.282T>G	p.Leu94=	synonymous_variant	4/57		NP_001316055.1
DNAJC13	XM_047447819.1	c.282T>G	p.Leu94=	synonymous_variant	4/57		XP_047303775.1
DNAJC13	XM_047447820.1	c.282T>G	p.Leu94=	synonymous_variant	4/56		XP_047303776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC13	ENST00000260818.11	c.282T>G	p.Leu94=	synonymous_variant	4/56	1	NM_015268.4	ENSP00000260818	P1
DNAJC13	ENST00000486798.5	n.347T>G		non_coding_transcript_exon_variant	4/20	1
DNAJC13	ENST00000650455.1	c.282T>G	p.Leu94=	synonymous_variant, NMD_transcript_variant	4/57			ENSP00000496825

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1737 AN: 152106 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.00953

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0119 AC: 2484 AN: 208172 Hom.: 26 AF XY: 0.0121 AC XY: 1384 AN XY: 113938

Gnomad AFR exome AF: 0.00335

Gnomad AMR exome AF: 0.00822

Gnomad ASJ exome AF: 0.0335

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00899

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.0157 AC: 22330 AN: 1422468 Hom.: 208 Cov.: 33 AF XY: 0.0154 AC XY: 10914 AN XY: 707294

Gnomad4 AFR exome AF: 0.00249

Gnomad4 AMR exome AF: 0.00760

Gnomad4 ASJ exome AF: 0.0314

Gnomad4 EAS exome AF: 0.0000520

Gnomad4 SAS exome AF: 0.00825

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.0175

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0114 AC: 1738 AN: 152224 Hom.: 18 Cov.: 32 AF XY: 0.0113 AC XY: 842 AN XY: 74432

Gnomad4 AFR AF: 0.00419

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.00953

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0164 Hom.: 15

Bravo AF: 0.0106

Asia WGS AF: 0.00318 AC: 11 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

DNAJC13-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.4
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs116489157; hg19: chr3-132166302;