Genetic Variant DNAJC28:p.Thr343Ser (chr21-33488366-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001040192.3(DNAJC28):c.1028C>G(p.Thr343Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. T343I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DNAJC28
NM_001040192.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.85

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07865912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC28	NM_001040192.3 link	c.1028C>G	p.Thr343Ser	missense_variant	Exon 2 of 2	ENST00000381947.4	NP_001035282.1	Q9NX36
DNAJC28	NM_001320746.3 link	c.1028C>G	p.Thr343Ser	missense_variant	Exon 2 of 2		NP_001307675.1	Q9NX36
DNAJC28	NM_017833.5 link	c.1028C>G	p.Thr343Ser	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.1028C>G	p.Thr343Ser	missense_variant	Exon 2 of 2	1	NM_001040192.3	ENSP00000371373.3	Q9NX36
DNAJC28	ENST00000314399.3 link	c.1028C>G	p.Thr343Ser	missense_variant	Exon 2 of 2	1		ENSP00000320303.3	Q9NX36
DNAJC28	ENST00000402202.1 link	c.1028C>G	p.Thr343Ser	missense_variant	Exon 2 of 2	5		ENSP00000385777.1	Q9NX36

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440090

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715842

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31804

American (AMR)

AF:

0.00

AC:

AN:

37874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25278

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.00

AC:

AN:

80830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106618

Other (OTH)

AF:

0.00

AC:

AN:

59400

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Benign

0.096

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0013

T;T;T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.37

M_CAP

Benign

0.0033

MetaRNN

Benign

0.079

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M;M;M

PhyloP100

1.8

PrimateAI

Benign

0.32

PROVEAN

Benign

0.32

.;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.17

.;T;T;T

Sift4G

Benign

0.70

T;T;T;T

Polyphen

0.068

B;B;B;B

Vest4

0.056

MutPred

0.35

Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);

MVP

0.24

MPC

0.031

ClinPred

0.092

GERP RS

4.3

Varity_R

0.067

gMVP

0.15

Mutation Taster

=95/5

polymorphism

(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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21-33488366-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