NM_005223.4:c.731G>A

Variant names:

• chr16-3657746-G-A
• rs1053874
• NM_005223.4:c.731G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 15/21 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, single submitter B:2 O:1
• Conservation: PhyloP100: -0.0550
• Publications: 66 publications found

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]

TRAP1 Gene-Disease associations (from GenCC):

• syndromic disease

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005223.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE1	NM_005223.4	MANE Select	c.731G>A	p.Arg244Gln	missense	Exon 8 of 9	NP_005214.2
	DNASE1	NM_001387139.1		c.800G>A	p.Arg267Gln	missense	Exon 8 of 9	NP_001374068.1
	DNASE1	NM_001351825.2		c.731G>A	p.Arg244Gln	missense	Exon 9 of 10	NP_001338754.1	P24855-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE1	ENST00000246949.10	TSL:1 MANE Select	c.731G>A	p.Arg244Gln	missense	Exon 8 of 9	ENSP00000246949.5	P24855-1
	DNASE1	ENST00000407479.5	TSL:1	c.731G>A	p.Arg244Gln	missense	Exon 9 of 10	ENSP00000385905.1	P24855-1
	DNASE1	ENST00000576792.1	TSL:3	c.119G>A	p.Arg40Gln	missense	Exon 2 of 2	ENSP00000461129.1	I3L4B8

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

GnomAD2 exomes AF: 0.360 AC: 90373 AN: 251148 AF XY: 0.353

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 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

African (AFR) AF: 0.761 AC: 25475 AN: 33480

American (AMR) AF: 0.350 AC: 15628 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7623 AN: 26136

East Asian (EAS) AF: 0.504 AC: 20003 AN: 39688

South Asian (SAS) AF: 0.400 AC: 34484 AN: 86254

European-Finnish (FIN) AF: 0.302 AC: 16090 AN: 53252

Middle Eastern (MID) AF: 0.344 AC: 1982 AN: 5762

European-Non Finnish (NFE) AF: 0.300 AC: 333127 AN: 1111908

Other (OTH) AF: 0.353 AC: 21315 AN: 60382

GnomAD4 genome AF: 0.439 AC: 66701 AN: 152000 Hom.: 17534 Cov.: 32 AF XY: 0.438 AC XY: 32513 AN XY: 74286

African (AFR) AF: 0.744 AC: 30864 AN: 41498

American (AMR) AF: 0.357 AC: 5446 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1034 AN: 3470

East Asian (EAS) AF: 0.458 AC: 2364 AN: 5158

South Asian (SAS) AF: 0.410 AC: 1976 AN: 4816

European-Finnish (FIN) AF: 0.305 AC: 3224 AN: 10554

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20525 AN: 67926

Other (OTH) AF: 0.415 AC: 876 AN: 2110

Alfa AF: 0.343 Hom.: 46337

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	DNASE1-related disorder (1)
-	-	1	not specified (1)
-	-	-	Systemic lupus erythematosus, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0088	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.055
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.27
Sift	Benign	0.69	T
Sift4G	Benign	0.79	T
Polyphen		0.0060	B
Vest4		0.11
MPC		0.0061
ClinPred		0.0024	T
GERP RS		4.5
PromoterAI		0.022	Neutral
Varity_R		0.094
gMVP		0.61
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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