5-139414161-C-T

Variant summary

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

The NM_152686.4(DNAJC18):​c.1064G>A​(p.Arg355His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R355C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DNAJC18
NM_152686.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56
Variant links:
Genes affected
DNAJC18 (HGNC:28429): (DnaJ heat shock protein family (Hsp40) member C18) Predicted to enable Hsp70 protein binding activity. Predicted to be involved in cellular response to misfolded protein; chaperone cofactor-dependent protein refolding; and ubiquitin-dependent ERAD pathway. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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=0.039183795).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAJC18NM_152686.4 linkc.1064G>A p.Arg355His missense_variant Exon 8 of 8 ENST00000302060.10 NP_689899.1 Q9H819

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAJC18ENST00000302060.10 linkc.1064G>A p.Arg355His missense_variant Exon 8 of 8 1 NM_152686.4 ENSP00000302843.5 Q9H819
DNAJC18ENST00000510770.1 linkn.370G>A non_coding_transcript_exon_variant Exon 2 of 2 2
DNAJC18ENST00000515559.2 linkn.77G>A non_coding_transcript_exon_variant Exon 1 of 2 3 ENSP00000485339.1 A0A096LP15
DNAJC18ENST00000508445.5 linkc.*144G>A downstream_gene_variant 3 ENSP00000426338.1 H0YA78

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152208
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251236
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461760
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152208
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 08, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1064G>A (p.R355H) alteration is located in exon 8 (coding exon 8) of the DNAJC18 gene. This alteration results from a G to A substitution at nucleotide position 1064, causing the arginine (R) at amino acid position 355 to be replaced by a histidine (H). 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
0.083
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
20
DANN
Benign
0.84
DEOGEN2
Benign
0.020
T
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.36
N
LIST_S2
Benign
0.74
T
M_CAP
Benign
0.0032
T
MetaRNN
Benign
0.039
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.41
N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.040
N
REVEL
Benign
0.094
Sift
Benign
0.52
T
Sift4G
Benign
0.53
T
Polyphen
0.0
B
Vest4
0.030
MVP
0.58
MPC
0.48
ClinPred
0.15
T
GERP RS
1.4
Varity_R
0.027
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs377218182; hg19: chr5-138749850; API