3-180984706-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_145261.4(DNAJC19):c.285A>C(p.Gly95=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,604,598 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (29 hom.)
• Consequence: DNAJC19 NM_145261.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.67

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 3-180984706-T-G is Benign according to our data. Variant chr3-180984706-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 137121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00452 (688/152188) while in subpopulation NFE AF= 0.00678 (461/68018). AF 95% confidence interval is 0.00627. There are 4 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC19	NM_145261.4	c.285A>C	p.Gly95=	synonymous_variant	6/6	ENST00000382564.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC19	ENST00000382564.8	c.285A>C	p.Gly95=	synonymous_variant	6/6	1	NM_145261.4	P1

Frequencies

GnomAD3 genomes AF: 0.00452 AC: 688 AN: 152070 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00678

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00489 AC: 1192 AN: 243624 Hom.: 5 AF XY: 0.00476 AC XY: 627 AN XY: 131732

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.00550

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00434

GnomAD4 exome AF: 0.00450 AC: 6538 AN: 1452410 Hom.: 29 Cov.: 28 AF XY: 0.00454 AC XY: 3280 AN XY: 722596

Gnomad4 AFR exome AF: 0.000361

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00595

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.00447

Gnomad4 OTH exome AF: 0.00377

GnomAD4 genome AF: 0.00452 AC: 688 AN: 152188 Hom.: 4 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74422

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00664

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.00678

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00482 Hom.: 2

Bravo AF: 0.00285

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	GeneDx	Oct 04, 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2020	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DNAJC19: BP4, BS2 -

3-methylglutaconic aciduria type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	13
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs17850540; hg19: chr3-180702494;