5-34929869-A-T

Variant summary

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

The NM_001012339.3(DNAJC21):c.50A>T(p.Glu17Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000281 in 1,421,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. E17G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: DNAJC21 NM_001012339.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.04

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]

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=0.40187776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC21	NM_001012339.3	c.50A>T	p.Glu17Val	missense_variant	1/12	ENST00000648817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC21	ENST00000648817.1	c.50A>T	p.Glu17Val	missense_variant	1/12		NM_001012339.3	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000909 AC: 2 AN: 219976 Hom.: 0 AF XY: 0.0000166 AC XY: 2 AN XY: 120714

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.000194

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1421744 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 707524

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: 0.00000366

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNAJC21-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2023

The DNAJC21 c.50A>T variant is predicted to result in the amino acid substitution p.Glu17Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-34929974-A-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 17 of the DNAJC21 protein (p.Glu17Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DNAJC21-related conditions. ClinVar contains an entry for this variant (Variation ID: 2094655). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
Polyphen		0.11	B;B;D;.
Vest4		0.29, 0.29
MutPred		0.51		Gain of MoRF binding (P = 0.0176);Gain of MoRF binding (P = 0.0176);Gain of MoRF binding (P = 0.0176);Gain of MoRF binding (P = 0.0176);
MVP		0.40
MPC		0.096
ClinPred		0.96	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.35
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs761693334; hg19: chr5-34929974;