NM_145261.4:c.316G>A

Variant names:

• chr3-180984675-C-T
• NM_145261.4:c.316G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_145261.4(DNAJC19):​c.316G>A​(p.Ala106Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAJC19 NM_145261.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80
• Publications: 0 publications found

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

ACMG classification

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, 0.915

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145261.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC19	NM_145261.4	MANE Select	c.316G>A	p.Ala106Thr	missense	Exon 6 of 6	NP_660304.1	A0A0S2Z5X1
	DNAJC19	NM_001190233.2		c.241G>A	p.Ala81Thr	missense	Exon 6 of 6	NP_001177162.1	Q96DA6-2
	DNAJC19	NR_033721.2		n.398G>A		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC19	ENST00000382564.8	TSL:1 MANE Select	c.316G>A	p.Ala106Thr	missense	Exon 6 of 6	ENSP00000372005.2	Q96DA6-1
	DNAJC19	ENST00000928270.1		c.313G>A	p.Ala105Thr	missense	Exon 6 of 6	ENSP00000598329.1
	DNAJC19	ENST00000479269.5	TSL:3	c.241G>A	p.Ala81Thr	missense	Exon 6 of 6	ENSP00000419191.1	Q96DA6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456554 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724606

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 85798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108486

Other (OTH) AF: 0.0000166 AC: 1 AN: 60140

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	3-methylglutaconic aciduria type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		5.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.80		Gain of methylation at K102 (P = 0.0831)
MVP		0.85
MPC		0.92
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.75
gMVP		0.95
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr3-180702463; COSMIC: COSV62801695; COSMIC: COSV62801695;