chr1-78013597-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BP4_Strong

The NM_007034.5(DNAJB4):c.758C>T(p.Thr253Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,593,436 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

DNAJB4
NM_007034.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.22

Publications

1 publications found

Variant links:

Genes affected

DNAJB4 (HGNC:14886): (DnaJ heat shock protein family (Hsp40) member B4) The protein encoded by this gene is a molecular chaperone, tumor suppressor, and member of the heat shock protein-40 family. The encoded protein binds the cell adhesion protein E-cadherin and targets it to the plasma membrane. This protein also binds incorrectly folded E-cadherin and targets it for endoplasmic reticulum-associated degradation. This gene is a strong tumor suppressor for colorectal carcinoma, and downregulation of it may serve as a good biomarker for predicting patient outcomes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

DNAJB4 links:

GIPC2 (HGNC:18177): (GIPC PDZ domain containing family member 2) Enables identical protein binding activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

GIPC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.2077 (below the threshold of 3.09). Trascript score misZ: 1.8136 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myopathy 21 with early respiratory failure, congenital myopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.040651947).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007034.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJB4	NM_007034.5	MANE Select	c.758C>T	p.Thr253Ile	missense	Exon 2 of 3	NP_008965.2
DNAJB4	NM_001317099.2		c.758C>T	p.Thr253Ile	missense	Exon 3 of 4	NP_001304028.1	Q9UDY4
DNAJB4	NM_001317100.2		c.638C>T	p.Thr213Ile	missense	Exon 3 of 4	NP_001304029.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAJB4	ENST00000370763.6	TSL:1 MANE Select	c.758C>T	p.Thr253Ile	missense	Exon 2 of 3	ENSP00000359799.5	Q9UDY4
DNAJB4	ENST00000867099.1		c.758C>T	p.Thr253Ile	missense	Exon 3 of 4	ENSP00000537158.1
DNAJB4	ENST00000867100.1		c.758C>T	p.Thr253Ile	missense	Exon 3 of 4	ENSP00000537159.1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000247

AC:

AN:

226722

AF XY:

0.000331

show subpopulations

Gnomad AFR exome

AF:

0.0000687

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000112

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000544

GnomAD4 exome

AF:

0.000266

AC:

383

AN:

1441210

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

212

AN XY:

716490

show subpopulations

African (AFR)

AF:

0.0000618

AC:

AN:

32384

American (AMR)

AF:

0.00

AC:

AN:

40824

Ashkenazi Jewish (ASJ)

AF:

0.0000790

AC:

AN:

25314

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39606

South Asian (SAS)

AF:

0.00128

AC:

106

AN:

82764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48492

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.000220

AC:

243

AN:

1106568

Other (OTH)

AF:

0.000369

AC:

AN:

59608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000854

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41522

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000159

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000298

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

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

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.018

Eigen_PC

Benign

0.0046

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.017

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.2

PhyloP100

2.2

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.18

Sift

Benign

0.047

Sift4G

Benign

0.061

Polyphen

0.19

Vest4

0.14

MutPred

0.50

Gain of catalytic residue at L258 (P = 0.0667)

MVP

0.31

MPC

0.24

ClinPred

0.084

GERP RS

1.0

Varity_R

0.15

gMVP

0.36

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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