12-55822730-C-T

Variant names:

• chr12-55822730-C-T
• rs768808249
• NM_032364.6:c.1637G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032364.6(DNAJC14):​c.1637G>A​(p.Arg546Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAJC14 NM_032364.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

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]

ENSG00000257390 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 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
DNAJC14	NM_032364.6	c.1637G>A	p.Arg546Lys	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000678005.2	NP_115740.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC14	ENST00000678005.2	c.1637G>A	p.Arg546Lys	missense_variant, splice_region_variant	Exon 5 of 7		NM_032364.6	ENSP00000504134.1
ENSG00000257390	ENST00000546837.5	c.524G>A	p.Arg175Lys	missense_variant, splice_region_variant	Exon 4 of 16	2		ENSP00000447000.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249602 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461622 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1637G>A (p.R546K) alteration is located in exon 5 (coding exon 4) of the DNAJC14 gene. This alteration results from a G to A substitution at nucleotide position 1637, causing the arginine (R) at amino acid position 546 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	Pathogenic	0.87
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;.;.;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;M;M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.034	D;D;D;.
Sift4G	Uncertain	0.018	D;D;D;.
Polyphen		0.61	P;P;P;.
Vest4		0.56
MutPred		0.42		Gain of methylation at R546 (P = 0.0082);Gain of methylation at R546 (P = 0.0082);Gain of methylation at R546 (P = 0.0082);.;
MVP		0.33
MPC		1.3
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.55
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs768808249; hg19: chr12-56216514;