chr16-4425930-C-A

Position:

• chr16-4425930-C-A

Variant summary

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

The NM_005147.6(DNAJA3):​c.49C>A​(p.Pro17Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAJA3 NM_005147.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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]

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=0.293375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJA3	NM_005147.6	c.49C>A	p.Pro17Thr	missense_variant	1/12	ENST00000262375.11
DNAJA3	NM_001135110.3	c.49C>A	p.Pro17Thr	missense_variant	1/11
DNAJA3	XM_047434875.1	c.49C>A	p.Pro17Thr	missense_variant	1/11
DNAJA3	NM_001286516.2	c.-62C>A		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJA3	ENST00000262375.11	c.49C>A	p.Pro17Thr	missense_variant	1/12	1	NM_005147.6	P3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1400764 Hom.: 0 Cov.: 79 AF XY: 0.00 AC XY: 0 AN XY: 692176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 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

Nov 27, 2023

The c.49C>A (p.P17T) alteration is located in exon 1 (coding exon 1) of the DNAJA3 gene. This alteration results from a C to A substitution at nucleotide position 49, causing the proline (P) at amino acid position 17 to be replaced by a threonine (T). 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	0.082
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.30	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.11
Sift	Benign	0.059	T;T;.
Sift4G	Benign	0.091	T;T;T
Polyphen		0.025	B;B;.
Vest4		0.28
MutPred		0.45		Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP		0.84
MPC		0.065
ClinPred		0.27	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1183117764; hg19: chr16-4475931;