rs142023670

chr3-180988083-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_145261.4(DNAJC19):c.69G>A(p.Leu23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,614,120 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (32 hom.)
• Consequence: DNAJC19 NM_145261.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.813

Genes affected

DNAJC19 (HGNC:30528): (DnaJ heat shock protein family (Hsp40) member C19) The protein encoded by this gene is thought to be part of a complex involved in the ATP-dependent transport of transit peptide-containing proteins from the inner cell membrane to the mitochondrial matrix. Defects in this gene are a cause of 3-methylglutaconic aciduria type 5 (MGA5), also known as dilated cardiomyopathy with ataxia (DCMA). Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 1, 2, 6, 10, 14 and 19. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 3-180988083-C-T is Benign according to our data. Variant chr3-180988083-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.813 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00321 (488/152238) while in subpopulation AMR AF= 0.00843 (129/15296). AF 95% confidence interval is 0.00725. There are 3 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC19	NM_145261.4	c.69G>A	p.Leu23=	synonymous_variant	3/6	ENST00000382564.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC19	ENST00000382564.8	c.69G>A	p.Leu23=	synonymous_variant	3/6	1	NM_145261.4	P1

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152120 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00468 AC: 1176 AN: 251452 Hom.: 12 AF XY: 0.00491 AC XY: 668 AN XY: 135920

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00656

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00967

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00455

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.00395 AC: 5769 AN: 1461882 Hom.: 32 Cov.: 31 AF XY: 0.00424 AC XY: 3084 AN XY: 727240

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00707

Gnomad4 ASJ exome AF: 0.00543

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00981

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00358

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.00321 AC: 488 AN: 152238 Hom.: 3 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74430

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00843

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00768

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00422 Hom.: 0

Bravo AF: 0.00356

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2017	Variant summary: The c.69G>A (p.Leu23=) in DNAJC19 gene is a synonymous change that involves a mildly conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in control dataset of ExAC at a frequency of 0.0044 (540/ 121392 chrs tested, including 4 homozygotes). These frequencies exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.000025). The variant of interest has not, to our knowledge, been reported in affected individuals via published reports, but is sited as Benign by a reputable database/clinical laboratory. Taking together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2014	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

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DNAJC19: BP4, BP7, BS2 -

3-methylglutaconic aciduria type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	10
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142023670; hg19: chr3-180705871;