Genetic Variant NM_001012339.3:c.23T>C (chr5-34929842-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

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

The NM_001012339.3(DNAJC21):c.23T>C(p.Leu8Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000707 in 1,414,256 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. L8R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

DNAJC21
NM_001012339.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.01

Publications

1 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: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Shwachman-Diamond syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DNAJC21 links:

LOC124900961 (HGNC:):

LOC124900961 links:

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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, 0.982

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012339.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJC21	NM_001012339.3	MANE Select	c.23T>C	p.Leu8Pro	missense	Exon 1 of 12	NP_001012339.2	Q5F1R6-1
DNAJC21	NM_194283.4		c.23T>C	p.Leu8Pro	missense	Exon 1 of 13	NP_919259.3	Q5F1R6-2
DNAJC21	NM_001348420.2		c.23T>C	p.Leu8Pro	missense	Exon 1 of 12	NP_001335349.1	Q5F1R6-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJC21	ENST00000648817.1	MANE Select	c.23T>C	p.Leu8Pro	missense	Exon 1 of 12	ENSP00000497410.1	Q5F1R6-1
DNAJC21	ENST00000966889.1		c.23T>C	p.Leu8Pro	missense	Exon 1 of 14	ENSP00000636948.1
DNAJC21	ENST00000382021.2	TSL:2	c.23T>C	p.Leu8Pro	missense	Exon 1 of 13	ENSP00000371451.2	Q5F1R6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000467

AC:

AN:

214308

AF XY:

0.00000846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414256

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29640

American (AMR)

AF:

0.00

AC:

AN:

41300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24542

East Asian (EAS)

AF:

0.00

AC:

AN:

34600

South Asian (SAS)

AF:

0.00

AC:

AN:

82840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5248

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088296

Other (OTH)

AF:

0.00

AC:

AN:

57688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

4.6

PhyloP100

7.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.83

MutPred

0.92

Gain of disorder (P = 0.0133)

MVP

0.93

MPC

0.46

ClinPred

1.0

GERP RS

4.0

PromoterAI

0.040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.93

Mutation Taster

=36/64

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over