21-33488465-C-T

Variant names:

• chr21-33488465-C-T
• rs182194192
• NM_001040192.3:c.929G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001040192.3(DNAJC28):​c.929G>A​(p.Arg310Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,610,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: DNAJC28 NM_001040192.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57
• Publications: 6 publications found

Genes affected

DNAJC28 (HGNC:1297): (DnaJ heat shock protein family (Hsp40) member C28) This gene encodes a member of the DnaJ heat shock protein family. The encoded protein, which contains a conserved N-terminal DnaJ domain, is thought to play a role in protein folding or act as a molecular chaperone protein. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10801345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC28	NM_001040192.3	c.929G>A	p.Arg310Gln	missense_variant	Exon 2 of 2	ENST00000381947.4	NP_001035282.1
DNAJC28	NM_001320746.3	c.929G>A	p.Arg310Gln	missense_variant	Exon 2 of 2		NP_001307675.1
DNAJC28	NM_017833.5	c.929G>A	p.Arg310Gln	missense_variant	Exon 2 of 2		NP_060303.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC28	ENST00000381947.4	c.929G>A	p.Arg310Gln	missense_variant	Exon 2 of 2	1	NM_001040192.3	ENSP00000371373.3
DNAJC28	ENST00000314399.3	c.929G>A	p.Arg310Gln	missense_variant	Exon 2 of 2	1		ENSP00000320303.3
DNAJC28	ENST00000402202.1	c.929G>A	p.Arg310Gln	missense_variant	Exon 2 of 2	5		ENSP00000385777.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000846 AC: 21 AN: 248172 AF XY: 0.0000671

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000764

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000782 AC: 114 AN: 1458258 Hom.: 0 Cov.: 33 AF XY: 0.0000565 AC XY: 41 AN XY: 725218

African (AFR) AF: 0.0000603 AC: 2 AN: 33164

American (AMR) AF: 0.00 AC: 0 AN: 43898

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26008

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39658

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000828 AC: 92 AN: 1110930

Other (OTH) AF: 0.0000332 AC: 2 AN: 60226

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74406

African (AFR) AF: 0.000120 AC: 5 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000665 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.929G>A (p.R310Q) alteration is located in exon 2 (coding exon 1) of the DNAJC28 gene. This alteration results from a G to A substitution at nucleotide position 929, causing the arginine (R) at amino acid position 310 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0064	T;T;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.8	M;M;M;M
PhyloP100		2.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	.;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.083	.;T;T;T
Sift4G	Benign	0.067	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.41
MVP		0.56
MPC		0.26
ClinPred		0.28	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.57
Mutation Taster		=85/15	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: rs182194192; hg19: chr21-34860772; COSMIC: COSV58721605; COSMIC: COSV58721605;