5-34929847-G-T

Variant names:

• chr5-34929847-G-T
• rs779102555
• NM_001012339.3:c.28G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001012339.3(DNAJC21):​c.28G>T​(p.Val10Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000021 in 1,426,522 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DNAJC21 NM_001012339.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78
• Publications: 0 publications found

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

LOC124900961 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC21	NM_001012339.3	c.28G>T	p.Val10Leu	missense_variant	Exon 1 of 12	ENST00000648817.1	NP_001012339.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC21	ENST00000648817.1	c.28G>T	p.Val10Leu	missense_variant	Exon 1 of 12		NM_001012339.3	ENSP00000497410.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000464 AC: 1 AN: 215674 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000326

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1426522 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 2 AN XY: 709702

African (AFR) AF: 0.00 AC: 0 AN: 30102

American (AMR) AF: 0.0000240 AC: 1 AN: 41752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25054

East Asian (EAS) AF: 0.00 AC: 0 AN: 35370

South Asian (SAS) AF: 0.00 AC: 0 AN: 83076

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5386

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095312

Other (OTH) AF: 0.00 AC: 0 AN: 58630

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 2081833). This variant has not been reported in the literature in individuals affected with DNAJC21-related conditions. This variant is present in population databases (rs779102555, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 10 of the DNAJC21 protein (p.Val10Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T;T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.97	.;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.41	N;N;N;N
PhyloP100		4.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.9	.;N;N;.
REVEL	Uncertain	0.47
Sift	Benign	0.13	.;T;T;.
Sift4G	Benign	0.11	.;T;T;.
Polyphen		0.85	P;P;P;.
Vest4		0.52, 0.56
MutPred		0.80		Gain of disorder (P = 0.0434);Gain of disorder (P = 0.0434);Gain of disorder (P = 0.0434);Gain of disorder (P = 0.0434);
MVP		0.61
MPC		0.074
ClinPred		0.83	D
GERP RS		0.017
PromoterAI		0.025	Neutral
Varity_R		0.33
gMVP		0.45
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs779102555; hg19: chr5-34929952;