Genetic Variant DNAJC14:p.Arg698Lys (chr12-55821993-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032364.6(DNAJC14):c.2093G>A(p.Arg698Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,612,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DNAJC14
NM_032364.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.56

Variant links:

Genes affected

DNAJC14 (HGNC:24581): (DnaJ heat shock protein family (Hsp40) member C14) Predicted to be involved in protein transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

DNAJC14 links:

ENSG00000257390 (HGNC:):

ENSG00000257390 links:

ORMDL2 (HGNC:16037): (ORMDL sphingolipid biosynthesis regulator 2) Involved in ceramide metabolic process. Acts upstream of or within negative regulation of ceramide biosynthetic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ORMDL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20465356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC14	NM_032364.6 link	c.2093G>A	p.Arg698Lys	missense_variant	Exon 7 of 7	ENST00000678005.2	NP_115740.5	Q6Y2X3A0A024RB64
ORMDL2	NM_014182.5 link	c.*1598C>T		downstream_gene_variant		ENST00000243045.10	NP_054901.1	Q53FV1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAJC14	ENST00000678005.2 link	c.2093G>A	p.Arg698Lys	missense_variant	Exon 7 of 7		NM_032364.6	ENSP00000504134.1	Q6Y2X3
ENSG00000257390	ENST00000546837.5 link	c.972+8G>A		splice_region_variant, intron_variant	Intron 6 of 15	2		ENSP00000447000.1	H0YHG0
ORMDL2	ENST00000243045.10 link	c.*1598C>T		downstream_gene_variant		1	NM_014182.5	ENSP00000243045.5	Q53FV1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460152

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726432

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2093G>A (p.R698K) alteration is located in exon 7 (coding exon 6) of the DNAJC14 gene. This alteration results from a G to A substitution at nucleotide position 2093, causing the arginine (R) at amino acid position 698 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.056

T;T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.72

T;.;.

M_CAP

Benign

0.0087

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M;M

PROVEAN

Benign

-0.78

N;N;N

REVEL

Benign

0.079

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.82

P;P;P

Vest4

0.14

MutPred

0.19

Gain of methylation at R698 (P = 0.0053);Gain of methylation at R698 (P = 0.0053);Gain of methylation at R698 (P = 0.0053);

MVP

0.33

MPC

1.2

ClinPred

0.87

GERP RS

5.6

Varity_R

0.28

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over