16-4426071-A-G

Position:

• chr16-4426071-A-G

Variant summary

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

The NM_005147.6(DNAJA3):​c.190A>G​(p.Arg64Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: DNAJA3 NM_005147.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

Genes affected

DNAJA3 (HGNC:11808): (DnaJ heat shock protein family (Hsp40) member A3) This gene encodes a member of the DNAJ/Hsp40 protein family. DNAJ/Hsp40 proteins stimulate the ATPase activity of Hsp70 chaperones and play critical roles in protein folding, degradation, and multimeric complex assembly. The encoded protein is localized to mitochondria and mediates several cellular processes including proliferation, survival and apoptotic signal transduction. The encoded protein also plays a critical role in tumor suppression through interactions with oncogenic proteins including ErbB2 and the p53 tumor suppressor protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]

DNAJA3 (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/exons	MANE	Protein	UniProt
DNAJA3	NM_005147.6	c.190A>G	p.Arg64Gly	missense_variant	1/12	ENST00000262375.11	NP_005138.3
DNAJA3	NM_001135110.3	c.190A>G	p.Arg64Gly	missense_variant	1/11		NP_001128582.1
DNAJA3	NM_001286516.2	c.80A>G	p.Glu27Gly	missense_variant	1/9		NP_001273445.1
DNAJA3	XM_047434875.1	c.190A>G	p.Arg64Gly	missense_variant	1/11		XP_047290831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJA3	ENST00000262375.11	c.190A>G	p.Arg64Gly	missense_variant	1/12	1	NM_005147.6	ENSP00000262375.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 34

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

Oct 26, 2022

The c.190A>G (p.R64G) alteration is located in exon 1 (coding exon 1) of the DNAJA3 gene. This alteration results from a A to G substitution at nucleotide position 190, causing the arginine (R) at amino acid position 64 to be replaced by a glycine (G). 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	0.096
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.039
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.85	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.097
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Vest4		0.60
MutPred		0.47		Loss of helix (P = 0.0068);
MVP		0.65
ClinPred		0.97	D
GERP RS		5.5

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: rs1596356479; hg19: chr16-4476072;