NM_001012339.3:c.15T>G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001012339.3(DNAJC21):​c.15T>G​(p.Tyr5*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000323 in 1,547,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAJC21 NM_001012339.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Shwachman-Diamond syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000302970 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 38 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-34929834-T-G is Pathogenic according to our data. Variant chr5-34929834-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2807142.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC21	NM_001012339.3	MANE Select	c.15T>G	p.Tyr5*	stop_gained	Exon 1 of 12	NP_001012339.2	Q5F1R6-1
	DNAJC21	NM_194283.4		c.15T>G	p.Tyr5*	stop_gained	Exon 1 of 13	NP_919259.3	Q5F1R6-2
	DNAJC21	NM_001348420.2		c.15T>G	p.Tyr5*	stop_gained	Exon 1 of 12	NP_001335349.1	Q5F1R6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC21	ENST00000648817.1	MANE Select	c.15T>G	p.Tyr5*	stop_gained	Exon 1 of 12	ENSP00000497410.1	Q5F1R6-1
	DNAJC21	ENST00000966889.1		c.15T>G	p.Tyr5*	stop_gained	Exon 1 of 14	ENSP00000636948.1
	DNAJC21	ENST00000382021.2	TSL:2	c.15T>G	p.Tyr5*	stop_gained	Exon 1 of 13	ENSP00000371451.2	Q5F1R6-2

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 150098 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397346 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 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: 0.0000201 AC: 1 AN: 49760

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

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078404

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

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 150098 Hom.: 0 Cov.: 29 AF XY: 0.0000137 AC XY: 1 AN XY: 73246

African (AFR) AF: 0.0000731 AC: 3 AN: 41040

American (AMR) AF: 0.00 AC: 0 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5000

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67366

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.0000614 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	-0.0090
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.59	D
PhyloP100		0.35
Vest4		0.12
GERP RS		-0.44
PromoterAI		0.18	Neutral
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;