Genetic Variant DNAJC19:p.Tyr21Cys (chr3-180988090-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001190233.2(DNAJC19):c.-14A>G variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

DNAJC19
NM_001190233.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.63

Publications

1 publications found

Variant links:

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]

DNAJC19 Gene-Disease associations (from GenCC):

3-methylglutaconic aciduria type 5
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

DNAJC19 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190233.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJC19	NM_145261.4	MANE Select	c.62A>G	p.Tyr21Cys	missense	Exon 3 of 6	NP_660304.1	A0A0S2Z5X1
DNAJC19	NM_001190233.2		c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	NP_001177162.1	Q96DA6-2
DNAJC19	NM_001190233.2		c.-14A>G		5_prime_UTR	Exon 3 of 6	NP_001177162.1	Q96DA6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJC19	ENST00000382564.8	TSL:1 MANE Select	c.62A>G	p.Tyr21Cys	missense	Exon 3 of 6	ENSP00000372005.2	Q96DA6-1
DNAJC19	ENST00000479269.5	TSL:3	c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	ENSP00000419191.1	Q96DA6-2
DNAJC19	ENST00000491873.5	TSL:2	c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000420767.1	Q96DA6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.022

MutationAssessor

Pathogenic

3.4

PhyloP100

4.6

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.31

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.94

MutPred

0.55

Loss of MoRF binding (P = 0.0809)

MVP

0.58

MPC

0.76

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.89

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over