5-34929844-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001012339.3(DNAJC21):​c.25G>T​(p.Gly9Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,425,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

DNAJC21
NM_001012339.3 missense

Scores

10
8
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.98

Publications

2 publications found
Variant links:
Genes affected
DNAJC21 (HGNC:27030): (DnaJ heat shock protein family (Hsp40) member C21) This gene encodes a member of the DNAJ heat shock protein 40 family of proteins that is characterized by two N-terminal tetratricopeptide repeat domains and a C-terminal DNAJ domain. This protein binds the precursor 45S ribosomal RNA and may be involved in early nuclear ribosomal RNA biogenesis and maturation of the 60S ribosomal subunit. Mutations in this gene result in Bone marrow failure syndrome 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2017]
DNAJC21 Gene-Disease associations (from GenCC):
  • bone marrow failure syndrome 3
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • Shwachman-Diamond syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAJC21NM_001012339.3 linkc.25G>T p.Gly9Trp missense_variant Exon 1 of 12 ENST00000648817.1 NP_001012339.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAJC21ENST00000648817.1 linkc.25G>T p.Gly9Trp missense_variant Exon 1 of 12 NM_001012339.3 ENSP00000497410.1 Q5F1R6-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
AF:
7.02e-7
AC:
1
AN:
1425418
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
709124
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30054
American (AMR)
AF:
0.00
AC:
0
AN:
41628
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25030
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35322
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82996
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51772
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5358
European-Non Finnish (NFE)
AF:
9.14e-7
AC:
1
AN:
1094690
Other (OTH)
AF:
0.00
AC:
0
AN:
58568
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
29
Alfa
AF:
0.00
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.53
D;D;.;.
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.97
.;D;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
0.71
D
MutationAssessor
Pathogenic
4.3
H;H;H;H
PhyloP100
4.0
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-5.3
.;D;D;.
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0030
.;D;D;.
Sift4G
Uncertain
0.0030
.;D;D;.
Polyphen
1.0
D;D;D;.
Vest4
0.55, 0.56
MutPred
0.86
Loss of disorder (P = 0.0094);Loss of disorder (P = 0.0094);Loss of disorder (P = 0.0094);Loss of disorder (P = 0.0094);
MVP
0.95
MPC
0.40
ClinPred
1.0
D
GERP RS
3.1
PromoterAI
0.12
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.76
gMVP
0.59
Mutation Taster
=46/54
disease causing

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

Other links and lift over

dbSNP: rs748031504; hg19: chr5-34929949; COSMIC: COSV100331377; COSMIC: COSV100331377; API