5-34929834-T-A

Variant names:

• chr5-34929834-T-A
• rs1396292043
• NM_001012339.3:c.15T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001012339.3(DNAJC21):​c.15T>A​(p.Tyr5*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAJC21 NM_001012339.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349
• 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

ENSG00000302970 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 37 pathogenic variants in the truncated region.
• 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.15T>A	p.Tyr5*	stop_gained	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.15T>A	p.Tyr5*	stop_gained	Exon 1 of 12		NM_001012339.3	ENSP00000497410.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1397346 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695538

African (AFR) AF: 0.00 AC: 0 AN: 28852

American (AMR) AF: 0.00 AC: 0 AN: 39862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23972

East Asian (EAS) AF: 0.00 AC: 0 AN: 33166

South Asian (SAS) AF: 0.00 AC: 0 AN: 81792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5066

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078404

Other (OTH) AF: 0.00 AC: 0 AN: 56472

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	-0.0090
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.56	D
PhyloP100		0.35
Vest4		0.12, 0.14
GERP RS		-0.44
PromoterAI		-0.0028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=30/170	disease causing (fs/PTC)

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: rs1396292043; hg19: chr5-34929939; COSMIC: COSV108851208; COSMIC: COSV108851208;