Genetic Variant NM_006145.3:c.12C>T (chr19-14518338-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_006145.3(DNAJB1):c.12C>T(p.Asp4Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,584,304 control chromosomes in the GnomAD database, including 85,744 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.35 ( 9468 hom., cov: 34)

Exomes 𝑓: 0.32 ( 76276 hom. )

Consequence

DNAJB1
NM_006145.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.168

Publications

17 publications found

Variant links:

Genes affected

DNAJB1 (HGNC:5270): (DnaJ heat shock protein family (Hsp40) member B1) This gene encodes a member of the DnaJ or Hsp40 (heat shock protein 40 kD) family of proteins. DNAJ family members are characterized by a highly conserved amino acid stretch called the 'J-domain' and function as one of the two major classes of molecular chaperones involved in a wide range of cellular events, such as protein folding and oligomeric protein complex assembly. The encoded protein is a molecular chaperone that stimulates the ATPase activity of Hsp70 heat-shock proteins in order to promote protein folding and prevent misfolded protein aggregation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

DNAJB1 links:

TECR (HGNC:4551): (trans-2,3-enoyl-CoA reductase) This gene encodes a multi-pass membrane protein that resides in the endoplasmic reticulum, and belongs to the steroid 5-alpha reductase family. The elongation of microsomal long and very long chain fatty acid consists of 4 sequential reactions. This protein catalyzes the final step, reducing trans-2,3-enoyl-CoA to saturated acyl-CoA. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Apr 2011]

TECR Gene-Disease associations (from GenCC):

autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
intellectual disability
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
intellectual disability, autosomal recessive 14
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TECR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP7

Synonymous conserved (PhyloP=0.168 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB1	NM_006145.3 link	c.12C>T	p.Asp4Asp	synonymous_variant	Exon 1 of 3	ENST00000254322.3	NP_006136.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB1	ENST00000254322.3 link	c.12C>T	p.Asp4Asp	synonymous_variant	Exon 1 of 3	1	NM_006145.3	ENSP00000254322.1

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52404

AN:

151942

Hom.:

9442

Cov.:

show subpopulations

Gnomad AFR

AF:

0.419

Gnomad AMI

AF:

0.475

Gnomad AMR

AF:

0.332

Gnomad ASJ

AF:

0.330

Gnomad EAS

AF:

0.0920

Gnomad SAS

AF:

0.433

Gnomad FIN

AF:

0.387

Gnomad MID

AF:

0.394

Gnomad NFE

AF:

0.309

Gnomad OTH

AF:

0.323

GnomAD2 exomes

AF:

0.341

AC:

74785

AN:

219030

AF XY:

0.342

show subpopulations

Gnomad AFR exome

AF:

0.420

Gnomad AMR exome

AF:

0.401

Gnomad ASJ exome

AF:

0.352

Gnomad EAS exome

AF:

0.0908

Gnomad FIN exome

AF:

0.399

Gnomad NFE exome

AF:

0.316

Gnomad OTH exome

AF:

0.334

GnomAD4 exome

AF:

0.321

AC:

460227

AN:

1432244

Hom.:

76276

Cov.:

AF XY:

0.324

AC XY:

231003

AN XY:

712738

show subpopulations

African (AFR)

AF:

0.423

AC:

13539

AN:

32026

American (AMR)

AF:

0.393

AC:

15633

AN:

39826

Ashkenazi Jewish (ASJ)

AF:

0.341

AC:

8427

AN:

24720

East Asian (EAS)

AF:

0.0845

AC:

3290

AN:

38914

South Asian (SAS)

AF:

0.427

AC:

35713

AN:

83574

European-Finnish (FIN)

AF:

0.392

AC:

18261

AN:

46548

Middle Eastern (MID)

AF:

0.359

AC:

1498

AN:

4176

European-Non Finnish (NFE)

AF:

0.313

AC:

344895

AN:

1103346

Other (OTH)

AF:

0.321

AC:

18971

AN:

59114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

15842

31683

47525

63366

79208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11396

22792

34188

45584

56980

<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:

0.345

AC:

52475

AN:

152060

Hom.:

9468

Cov.:

AF XY:

0.348

AC XY:

25900

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.419

AC:

17401

AN:

41484

American (AMR)

AF:

0.332

AC:

5079

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

1146

AN:

3470

East Asian (EAS)

AF:

0.0924

AC:

477

AN:

5164

South Asian (SAS)

AF:

0.433

AC:

2086

AN:

4822

European-Finnish (FIN)

AF:

0.387

AC:

4096

AN:

10572

Middle Eastern (MID)

AF:

0.390

AC:

113

AN:

290

European-Non Finnish (NFE)

AF:

0.309

AC:

20973

AN:

67946

Other (OTH)

AF:

0.320

AC:

674

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1775

3550

5324

7099

8874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

512

1024

1536

2048

2560

<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:

0.325

Hom.:

1727

Bravo

AF:

0.342

Asia WGS

AF:

0.273

AC:

948

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.7

(source)

DANN

Benign

0.96

PhyloP100

0.17

PromoterAI

-0.010

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Mutation Taster

=99/1

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over