16-3655379-G-T

Variant names:

• chr16-3655379-G-T
• rs8176927
• NM_005223.4:c.6G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005223.4(DNASE1):​c.6G>T​(p.Arg2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00965 in 1,614,140 control chromosomes in the GnomAD database, including 483 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.034 (209 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (274 hom.)
• Consequence: DNASE1 NM_005223.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0390
• Publications: 12 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028059185).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNASE1	NM_005223.4	c.6G>T	p.Arg2Ser	missense_variant	Exon 2 of 9	ENST00000246949.10	NP_005214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE1	ENST00000246949.10	c.6G>T	p.Arg2Ser	missense_variant	Exon 2 of 9	1	NM_005223.4	ENSP00000246949.5

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5151 AN: 152218 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00407

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0130 AC: 3271 AN: 250674 AF XY: 0.0115

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00474

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00713 AC: 10419 AN: 1461804 Hom.: 274 Cov.: 33 AF XY: 0.00695 AC XY: 5056 AN XY: 727216

African (AFR) AF: 0.110 AC: 3685 AN: 33480

American (AMR) AF: 0.0131 AC: 588 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 548 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0108 AC: 931 AN: 86258

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53352

Middle Eastern (MID) AF: 0.0336 AC: 194 AN: 5768

European-Non Finnish (NFE) AF: 0.00325 AC: 3615 AN: 1111998

Other (OTH) AF: 0.0139 AC: 837 AN: 60392

GnomAD4 genome AF: 0.0338 AC: 5153 AN: 152336 Hom.: 209 Cov.: 32 AF XY: 0.0334 AC XY: 2487 AN XY: 74486

African (AFR) AF: 0.103 AC: 4269 AN: 41576

American (AMR) AF: 0.0256 AC: 391 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.00407 AC: 277 AN: 68034

Other (OTH) AF: 0.0412 AC: 87 AN: 2112

Alfa AF: 0.0157 Hom.: 239

Bravo AF: 0.0391

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.104 AC: 458

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.0144 AC: 1747

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00741

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.8
DANN	Benign	0.95
DEOGEN2	Benign	0.076	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.0	.;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		-0.039
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.078
Sift	Benign	0.087	T;T
Sift4G	Benign	0.16	T;T
Vest4		0.058
ClinPred		0.0017	T
GERP RS		0.59
Varity_R		0.11
gMVP		0.83
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8176927; hg19: chr16-3705380; COSMIC: COSV55912951; COSMIC: COSV55912951;