16-4425942-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005147.6(DNAJA3):​c.61G>A​(p.Ala21Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,561,974 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00077 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

DNAJA3
NM_005147.6 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.011912167).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAJA3NM_005147.6 linkuse as main transcriptc.61G>A p.Ala21Thr missense_variant 1/12 ENST00000262375.11 NP_005138.3 Q96EY1-1Q53G26Q59E88
DNAJA3NM_001135110.3 linkuse as main transcriptc.61G>A p.Ala21Thr missense_variant 1/11 NP_001128582.1 Q96EY1-2B3KM81
DNAJA3XM_047434875.1 linkuse as main transcriptc.61G>A p.Ala21Thr missense_variant 1/11 XP_047290831.1
DNAJA3NM_001286516.2 linkuse as main transcriptc.-50G>A 5_prime_UTR_variant 1/9 NP_001273445.1 Q96EY1-3B3KM81

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAJA3ENST00000262375.11 linkuse as main transcriptc.61G>A p.Ala21Thr missense_variant 1/121 NM_005147.6 ENSP00000262375.4 Q96EY1-1

Frequencies

GnomAD3 genomes
AF:
0.000775
AC:
118
AN:
152236
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00275
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000138
AC:
23
AN:
166778
Hom.:
0
AF XY:
0.0000769
AC XY:
7
AN XY:
91000
show subpopulations
Gnomad AFR exome
AF:
0.00245
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000825
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000148
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000116
AC:
163
AN:
1409620
Hom.:
1
Cov.:
78
AF XY:
0.000108
AC XY:
75
AN XY:
697484
show subpopulations
Gnomad4 AFR exome
AF:
0.00316
Gnomad4 AMR exome
AF:
0.000108
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000868
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000304
Gnomad4 OTH exome
AF:
0.000257
GnomAD4 genome
AF:
0.000775
AC:
118
AN:
152354
Hom.:
0
Cov.:
34
AF XY:
0.000752
AC XY:
56
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.00274
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000854
Hom.:
0
Bravo
AF:
0.000824
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00169
AC:
7
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000856
AC:
10
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 19, 2023The c.61G>A (p.A21T) alteration is located in exon 1 (coding exon 1) of the DNAJA3 gene. This alteration results from a G to A substitution at nucleotide position 61, causing the alanine (A) at amino acid position 21 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
0.079
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.10
T;.;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.044
FATHMM_MKL
Benign
0.51
D
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.012
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.9
L;L;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.66
N;N;.
REVEL
Benign
0.054
Sift
Benign
0.075
T;T;.
Sift4G
Benign
0.52
T;T;T
Polyphen
0.0010
B;B;.
Vest4
0.21
MVP
0.83
MPC
0.058
ClinPred
0.037
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.10
gMVP
0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199789349; hg19: chr16-4475943; API