Genetic Variant DNAJA1:c.758+337T>C (chr9-33034667-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001539.4(DNAJA1):c.758+337T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,258 control chromosomes in the GnomAD database, including 1,316 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 0.12 ( 1316 hom., cov: 32)

Consequence

DNAJA1
NM_001539.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.102

Publications

8 publications found

Variant links:

Genes affected

DNAJA1 (HGNC:5229): (DnaJ heat shock protein family (Hsp40) member A1) This gene encodes a member of the DnaJ family of proteins, which act as heat shock protein 70 cochaperones. Heat shock proteins facilitate protein folding, trafficking, prevention of aggregation, and proteolytic degradation. Members of this family are characterized by a highly conserved N-terminal J domain, a glycine/phenylalanine-rich region, four CxxCxGxG zinc finger repeats, and a C-terminal substrate-binding domain. The J domain mediates the interaction with heat shock protein 70 to recruit substrates and regulate ATP hydrolysis activity. In humans, this gene has been implicated in positive regulation of virus replication through co-option by the influenza A virus. Several pseudogenes of this gene are found on other chromosomes. [provided by RefSeq, Sep 2015]

DNAJA1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DNAJA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJA1	NM_001539.4 link	c.758+337T>C		intron_variant	Intron 6 of 8	ENST00000330899.5	NP_001530.1
DNAJA1	NM_001314039.2 link	c.287+337T>C		intron_variant	Intron 5 of 7		NP_001300968.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
DNAJA1	ENST00000330899.5 link	c.758+337T>C	intron_variant	Intron 6 of 8	1	NM_001539.4	ENSP00000369127.3
DNAJA1	ENST00000465677.1 link	n.71+337T>C	intron_variant	Intron 1 of 2	2
DNAJA1	ENST00000495015.5 link	n.213+337T>C	intron_variant	Intron 2 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.120

AC:

18183

AN:

152140

Hom.:

1324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0356

Gnomad AMI

AF:

0.222

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.179

Gnomad SAS

AF:

0.254

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.153

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.119

AC:

18169

AN:

152258

Hom.:

1316

Cov.:

AF XY:

0.120

AC XY:

8970

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0354

AC:

1473

AN:

41562

American (AMR)

AF:

0.163

AC:

2489

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

584

AN:

3470

East Asian (EAS)

AF:

0.178

AC:

925

AN:

5186

South Asian (SAS)

AF:

0.253

AC:

1221

AN:

4830

European-Finnish (FIN)

AF:

0.112

AC:

1184

AN:

10602

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.143

AC:

9697

AN:

68014

Other (OTH)

AF:

0.154

AC:

325

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

812

1624

2436

3248

4060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

218

436

654

872

1090

<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:

0.145

Hom.:

2875

Bravo

AF:

0.118

Asia WGS

AF:

0.233

AC:

810

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.2

(source)

DANN

Benign

0.80

PhyloP100

0.10

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over