rs1053874

chr16-3657746-G-Achr16-3657746-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.0550

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]

LOC124903631 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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/exons	MANE	UniProt
DNASE1	NM_005223.4	c.731G>A	p.Arg244Gln	missense_variant	8/9	ENST00000246949.10
LOC124903631	XR_007064954.1	n.22C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNASE1	ENST00000246949.10	c.731G>A	p.Arg244Gln	missense_variant	8/9	1	NM_005223.4	P1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66596 AN: 151882 Hom.: 17497 Cov.: 32

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

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.: 63 AF XY: 0.326 AC XY: 236893 AN XY: 727092

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.: 32 AF XY: 0.438 AC XY: 32513 AN XY: 74286

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:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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

risk factor, no assertion criteria provided

literature only

OMIM

Oct 15, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.61	T
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	N
MetaRNN	Benign	0.0000022	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.40	T
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	T
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

Other links and lift over

dbSNP: rs1053874; hg19: chr16-3707747; COSMIC: COSV55912793; COSMIC: COSV55912793;