Genetic Variant DNAJC28:p.Arg202Gly (chr21-33488790-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001040192.3(DNAJC28):c.604C>G(p.Arg202Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R202C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DNAJC28
NM_001040192.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.33

Publications

0 publications found

Variant links:

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]

DNAJC28 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC28	NM_001040192.3 link	c.604C>G	p.Arg202Gly	missense_variant	Exon 2 of 2	ENST00000381947.4	NP_001035282.1	Q9NX36
DNAJC28	NM_001320746.3 link	c.604C>G	p.Arg202Gly	missense_variant	Exon 2 of 2		NP_001307675.1	Q9NX36
DNAJC28	NM_017833.5 link	c.604C>G	p.Arg202Gly	missense_variant	Exon 2 of 2		NP_060303.2	Q9NX36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAJC28	ENST00000381947.4 link	c.604C>G	p.Arg202Gly	missense_variant	Exon 2 of 2	1	NM_001040192.3	ENSP00000371373.3	Q9NX36
DNAJC28	ENST00000314399.3 link	c.604C>G	p.Arg202Gly	missense_variant	Exon 2 of 2	1		ENSP00000320303.3	Q9NX36
DNAJC28	ENST00000402202.1 link	c.604C>G	p.Arg202Gly	missense_variant	Exon 2 of 2	5		ENSP00000385777.1	Q9NX36

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461474

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111936

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Pathogenic

3.0

M;M;M;M

PhyloP100

7.3

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.9

.;D;D;D

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.92

MutPred

0.43

Loss of MoRF binding (P = 0.025);Loss of MoRF binding (P = 0.025);Loss of MoRF binding (P = 0.025);Loss of MoRF binding (P = 0.025);

MVP

0.63

MPC

0.27

ClinPred

1.0

GERP RS

5.4

Varity_R

0.88

gMVP

0.75

Mutation Taster

=21/79

disease causing

(source)

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

Publications

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chr21-33488790-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over