rs1441391830

Variant names:

• chr5-34929862-A-C
• rs1441391830
• NM_001012339.3:c.43A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-34929862-A-C
• chr5-34929862-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001012339.3(DNAJC21):​c.43A>C​(p.Ser15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,398,960 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 (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: DNAJC21 NM_001012339.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.197
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39472225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC21	NM_001012339.3	c.43A>C	p.Ser15Arg	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.43A>C	p.Ser15Arg	missense_variant	Exon 1 of 12		NM_001012339.3	ENSP00000497410.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00 AC: 0 AN: 218568 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1398960 Hom.: 0 Cov.: 31 AF XY: 0.00000431 AC XY: 3 AN XY: 696546

African (AFR) AF: 0.00 AC: 0 AN: 29224

American (AMR) AF: 0.00 AC: 0 AN: 41066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23910

East Asian (EAS) AF: 0.00 AC: 0 AN: 33624

South Asian (SAS) AF: 0.00 AC: 0 AN: 83086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5370

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1078974

Other (OTH) AF: 0.00 AC: 0 AN: 56590

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 19, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with arginine at codon 15 of the DNAJC21 protein (p.Ser15Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DNAJC21-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.84	.;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.8	M;M;M;M
PhyloP100		0.20
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.6	.;D;D;.
REVEL	Benign	0.21
Sift	Benign	0.12	.;T;T;.
Sift4G	Benign	0.35	.;T;T;.
Polyphen		0.91	P;P;D;.
Vest4		0.19, 0.22
MutPred		0.56		Loss of phosphorylation at S15 (P = 0.0085);Loss of phosphorylation at S15 (P = 0.0085);Loss of phosphorylation at S15 (P = 0.0085);Loss of phosphorylation at S15 (P = 0.0085);
MVP		0.51
MPC		0.37
ClinPred		0.88	D
GERP RS		2.8
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.48
Mutation Taster		=72/28	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: rs1441391830; hg19: chr5-34929967;