1-28201357-C-T

Variant names:

• chr1-28201357-C-T
• NM_014280.3:c.653G>A

Variant summary

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

The NM_014280.3(DNAJC8):​c.653G>A​(p.Gly218Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJC8 NM_014280.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56

Genes affected

DNAJC8 (HGNC:15470): (DnaJ heat shock protein family (Hsp40) member C8) Enables Hsp70 protein binding activity. Located in cytosol; intercellular bridge; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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
DNAJC8	NM_014280.3	c.653G>A	p.Gly218Asp	missense_variant	Exon 9 of 9	ENST00000263697.6	NP_055095.2
DNAJC8	NR_159454.1	n.806G>A		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC8	ENST00000263697.6	c.653G>A	p.Gly218Asp	missense_variant	Exon 9 of 9	1	NM_014280.3	ENSP00000263697.4
DNAJC8	ENST00000489277.5	n.802G>A		non_coding_transcript_exon_variant	Exon 10 of 10	1		ENSP00000518780.1
DNAJC8	ENST00000603289.5	c.182G>A	p.Gly61Asp	missense_variant	Exon 3 of 5	5		ENSP00000474440.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.653G>A (p.G218D) alteration is located in exon 9 (coding exon 9) of the DNAJC8 gene. This alteration results from a G to A substitution at nucleotide position 653, causing the glycine (G) at amino acid position 218 to be replaced by an aspartic acid (D). 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	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0066	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.30
Sift	Benign	0.26	T
Sift4G	Benign	0.53	T
Polyphen		0.82	P
Vest4		0.84
MutPred		0.14		Loss of MoRF binding (P = 0.0644);
MVP		0.85
MPC		1.1
ClinPred		0.81	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.53

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-28527868;