10-21904567-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022365.4(DNAJC1):c.775G>C(p.Glu259Gln) 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. 14/21 in silico tools predict 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: 3.84

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13910389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC1	NM_022365.4	c.775G>C	p.Glu259Gln	missense_variant	7/12	ENST00000376980.8
DNAJC1	XM_011519614.4	c.775G>C	p.Glu259Gln	missense_variant	7/10
DNAJC1	XM_017016536.3	c.775G>C	p.Glu259Gln	missense_variant	7/9
DNAJC1	XM_047425628.1	c.775G>C	p.Glu259Gln	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC1	ENST00000376980.8	c.775G>C	p.Glu259Gln	missense_variant	7/12	1	NM_022365.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.775G>C (p.E259Q) alteration is located in exon 7 (coding exon 7) of the DNAJC1 gene. This alteration results from a G to C substitution at nucleotide position 775, causing the glutamic acid (E) at amino acid position 259 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.039
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.075
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Polyphen		0.047	B
Vest4		0.39
MutPred		0.20		Loss of ubiquitination at K258 (P = 0.0657);
MVP		0.64
MPC		0.20
ClinPred		0.70	D
GERP RS		4.8
Varity_R		0.11
gMVP		0.25

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

Other links and lift over

dbSNP: rs1299762979; hg19: chr10-22193496;