rs372756221

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145261.4(DNAJC19):c.1A>G(p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,586,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

DNAJC19
NM_145261.4 start_lost, splice_region

Scores

Splicing: ADA: 0.05568

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38

Publications

0 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 links:

SOX2-OT (HGNC:20209): (SOX2 overlapping transcript) This gene produces alternatively spliced long non-coding RNAs. These RNAs were observed to be upregulated in tumor cells and positively correlated to expression of the SRY-box 2 gene. Overexpression of these transcripts may promote cell proliferation. [provided by RefSeq, Dec 2017]

SOX2-OT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC19	NM_145261.4 link	c.1A>G	p.Met1?	start_lost, splice_region_variant	Exon 1 of 6	ENST00000382564.8	NP_660304.1	Q96DA6-1A0A0S2Z5X1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC19	ENST00000382564.8 link	c.1A>G	p.Met1?	start_lost, splice_region_variant	Exon 1 of 6	1	NM_145261.4	ENSP00000372005.2		Q96DA6-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000297

AC:

AN:

201858

AF XY:

0.0000459

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000691

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000418

AC:

AN:

1434780

Hom.:

Cov.:

AF XY:

0.0000338

AC XY:

AN XY:

711002

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

33040

American (AMR)

AF:

0.00

AC:

AN:

41040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25408

East Asian (EAS)

AF:

0.00

AC:

AN:

38552

South Asian (SAS)

AF:

0.00

AC:

AN:

81872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0000528

AC:

AN:

1098898

Other (OTH)

AF:

0.0000169

AC:

AN:

59328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000417

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

3-methylglutaconic aciduria type 5

Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the DNAJC19 mRNA. The next in-frame methionine is located at codon 26. This variant is present in population databases (rs372756221, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with DNAJC19-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Benign

-0.86

PhyloP100

3.4

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.10

T;T

Sift4G

Benign

0.091

T;D

Polyphen

0.0

B;.

Vest4

0.94

MVP

0.40

ClinPred

0.63

GERP RS

4.7

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.54

gMVP

0.76

Mutation Taster

=32/168

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.056

dbscSNV1_RF

Benign

0.34

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over