NM_005223.4:c.731G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005223.4(DNASE1):c.731G>A(p.Arg244Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,613,564 control chromosomes in the GnomAD database, including 100,282 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.44 ( 17534 hom., cov: 32)

Exomes 𝑓: 0.33 ( 82748 hom. )

Consequence

DNASE1
NM_005223.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: -0.0550

Variant links:

Genes affected

DNASE1 (HGNC:2956): (deoxyribonuclease 1) This gene encodes a member of the DNase family. This protein is stored in the zymogen granules of the nuclear envelope and functions by cleaving DNA in an endonucleolytic manner. At least six autosomal codominant alleles have been characterized, DNASE1*1 through DNASE1*6, and the sequence of DNASE1*2 represented in this record. Mutations in this gene have been associated with systemic lupus erythematosus (SLE), an autoimmune disease. A recombinant form of this protein is used to treat the one of the symptoms of cystic fibrosis by hydrolyzing the extracellular DNA in sputum and reducing its viscosity. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

DNASE1 links:

LOC124903631 (HGNC:):

LOC124903631 links:

TRAP1 (HGNC:16264): (TNF receptor associated protein 1) This gene encodes a mitochondrial chaperone protein that is member of the heat shock protein 90 (HSP90) family. The encoded protein has ATPase activity and interacts with tumor necrosis factor type I. This protein may function in regulating cellular stress responses. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

TRAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.1568667E-6).

BP6

Variant 16-3657746-G-A is Benign according to our data. Variant chr16-3657746-G-A is described in ClinVar as [Benign]. Clinvar id is 16852.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE1	NM_005223.4 link	c.731G>A	p.Arg244Gln	missense_variant	Exon 8 of 9	ENST00000246949.10	NP_005214.2	P24855-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE1	ENST00000246949.10 link	c.731G>A	p.Arg244Gln	missense_variant	Exon 8 of 9	1	NM_005223.4	ENSP00000246949.5		P24855-1

Frequencies

GnomAD3 genomes

AF:

0.438

AC:

66596

AN:

151882

Hom.:

17497

Cov.:

show subpopulations

Gnomad AFR

AF:

0.744

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.356

Gnomad ASJ

AF:

0.298

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.409

Gnomad FIN

AF:

0.305

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.412

GnomAD3 exomes

AF:

0.360

AC:

90373

AN:

251148

Hom.:

18114

AF XY:

0.353

AC XY:

47976

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.754

Gnomad AMR exome

AF:

0.352

Gnomad ASJ exome

AF:

0.295

Gnomad EAS exome

AF:

0.450

Gnomad SAS exome

AF:

0.405

Gnomad FIN exome

AF:

0.306

Gnomad NFE exome

AF:

0.297

Gnomad OTH exome

AF:

0.322

GnomAD4 exome

AF:

0.325

AC:

475727

AN:

1461564

Hom.:

82748

Cov.:

AF XY:

0.326

AC XY:

236893

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.761

Gnomad4 AMR exome

AF:

0.350

Gnomad4 ASJ exome

AF:

0.292

Gnomad4 EAS exome

AF:

0.504

Gnomad4 SAS exome

AF:

0.400

Gnomad4 FIN exome

AF:

0.302

Gnomad4 NFE exome

AF:

0.300

Gnomad4 OTH exome

AF:

0.353

GnomAD4 genome

AF:

0.439

AC:

66701

AN:

152000

Hom.:

17534

Cov.:

AF XY:

0.438

AC XY:

32513

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.744

Gnomad4 AMR

AF:

0.357

Gnomad4 ASJ

AF:

0.298

Gnomad4 EAS

AF:

0.458

Gnomad4 SAS

AF:

0.410

Gnomad4 FIN

AF:

0.305

Gnomad4 NFE

AF:

0.302

Gnomad4 OTH

AF:

0.415

Alfa

AF:

0.322

Hom.:

18360

Bravo

AF:

0.456

TwinsUK

AF:

0.304

AC:

1129

ALSPAC

AF:

0.301

AC:

1160

ESP6500AA

AF:

0.740

AC:

3251

ESP6500EA

AF:

0.303

AC:

2606

ExAC

AF:

0.371

AC:

45034

EpiCase

AF:

0.302

EpiControl

AF:

0.297

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 65% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. -

DNASE1-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Systemic lupus erythematosus, susceptibility to

Other:1

Oct 15, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.6

DANN

Benign

0.66

DEOGEN2

Benign

0.18

T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0088

LIST_S2

Benign

0.14

.;T;T

MetaRNN

Benign

0.0000022

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.6

N;N;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.43

N;N;.

REVEL

Benign

0.27

Sift

Benign

0.69

T;T;.

Sift4G

Benign

0.79

T;T;T

Polyphen

0.0060

B;B;.

Vest4

0.11

MPC

0.0061

ClinPred

0.0024

GERP RS

4.5

Varity_R

0.094

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over