Genetic Variant DNAJA4:p.Arg305Cys (chr15-78280080-C-T) – 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_001130182.2(DNAJA4):c.913C>T(p.Arg305Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DNAJA4
NM_001130182.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.603

Publications

3 publications found

Variant links:

Genes affected

DNAJA4 (HGNC:14885): (DnaJ heat shock protein family (Hsp40) member A4) Enables chaperone binding activity and unfolded protein binding activity. Involved in several processes, including negative regulation of endothelial cell migration; negative regulation of inclusion body assembly; and protein refolding. Located in cytosol and membrane. [provided by Alliance of Genome Resources, Apr 2022]

DNAJA4 links:

SKIC8 (HGNC:30300): (SKI8 subunit of superkiller complex) WDR61 is a subunit of the human PAF and SKI complexes, which function in transcriptional regulation and are involved in events downstream of RNA synthesis, such as RNA surveillance (Zhu et al., 2005 [PubMed 16024656]).[supplied by OMIM, Mar 2008]

SKIC8 links:

Genome browser will be placed here

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=0.19039989).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130182.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJA4	NM_001130182.2	MANE Select	c.913C>T	p.Arg305Cys	missense	Exon 6 of 7	NP_001123654.1	Q8WW22-1
DNAJA4	NM_018602.4		c.1000C>T	p.Arg334Cys	missense	Exon 7 of 8	NP_061072.3
DNAJA4	NM_001387384.1		c.967C>T	p.Arg323Cys	missense	Exon 8 of 9	NP_001374313.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJA4	ENST00000394852.8	TSL:1 MANE Select	c.913C>T	p.Arg305Cys	missense	Exon 6 of 7	ENSP00000378321.3	Q8WW22-1
DNAJA4	ENST00000394855.7	TSL:1	c.1000C>T	p.Arg334Cys	missense	Exon 7 of 8	ENSP00000378324.3	Q8WW22-2
DNAJA4	ENST00000446172.2	TSL:1	c.832C>T	p.Arg278Cys	missense	Exon 6 of 7	ENSP00000413499.2	Q8WW22-3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.000957

GnomAD2 exomes

AF:

0.0000437

AC:

AN:

251472

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000463

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.17

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.77

M_CAP

Benign

0.037

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.8

PhyloP100

0.60

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.88

REVEL

Benign

0.088

Sift

Benign

0.20

Sift4G

Benign

0.20

Polyphen

0.95

Vest4

0.28

MVP

0.54

MPC

0.38

ClinPred

0.15

GERP RS

2.3

Varity_R

0.054

gMVP

0.57

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over