NM_022365.4:c.829A>G

Variant names:

• chr10-21882431-T-C
• NM_022365.4:c.829A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022365.4(DNAJC1):​c.829A>G​(p.Lys277Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNAJC1 NM_022365.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.41

Genes affected

DNAJC1 (HGNC:20090): (DnaJ heat shock protein family (Hsp40) member C1) The membrane protein encoded by this gene is a DNAJ-like heat shock protein that binds the molecular chaperone BiP. In addition, the encoded protein contains two SANT domains that have been shown to bind serpin alpha1-antichymotrypsin and inter-alpha trypsin inhibitor heavy chain 4. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3563272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC1	NM_022365.4	c.829A>G	p.Lys277Glu	missense_variant	Exon 8 of 12	ENST00000376980.8	NP_071760.2
DNAJC1	XM_011519614.4	c.829A>G	p.Lys277Glu	missense_variant	Exon 8 of 10		XP_011517916.1
DNAJC1	XM_017016536.3	c.829A>G	p.Lys277Glu	missense_variant	Exon 8 of 9		XP_016872025.1
DNAJC1	XM_047425628.1	c.829A>G	p.Lys277Glu	missense_variant	Exon 8 of 10		XP_047281584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC1	ENST00000376980.8	c.829A>G	p.Lys277Glu	missense_variant	Exon 8 of 12	1	NM_022365.4	ENSP00000366179.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.829A>G (p.K277E) alteration is located in exon 8 (coding exon 8) of the DNAJC1 gene. This alteration results from a A to G substitution at nucleotide position 829, causing the lysine (K) at amino acid position 277 to be replaced by a glutamic acid (E). 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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.21
Sift	Benign	0.086	T
Sift4G	Uncertain	0.013	D
Polyphen		0.95	P
Vest4		0.47
MutPred		0.23		Loss of methylation at K277 (P = 0.0048);
MVP		0.78
MPC		0.86
ClinPred		0.85	D
GERP RS		6.0
Varity_R		0.28
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-22171360;