rs35677470

Positions:

• chr3-58197909-G-A
• chr3-58197909-G-C

Variant summary

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

The NM_004944.4(DNASE1L3):​c.616C>T​(p.Arg206Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0661 in 1,614,064 control chromosomes in the GnomAD database, including 4,010 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.046 (213 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3797 hom.)
• Consequence: DNASE1L3 NM_004944.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.53

Genes affected

DNASE1L3 (HGNC:2959): (deoxyribonuclease 1 like 3) This gene encodes a member of the deoxyribonuclease I family. The encoded protein hydrolyzes DNA, is not inhibited by actin, and mediates the breakdown of DNA during apoptosis. Mutations in this gene are a cause of systemic lupus erythematosus-16. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02154231).
• BP6: Variant 3-58197909-G-A is Benign according to our data. Variant chr3-58197909-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1146799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNASE1L3	NM_004944.4	c.616C>T	p.Arg206Cys	missense_variant	6/8	ENST00000394549.7
DNASE1L3	NM_001256560.2	c.526C>T	p.Arg176Cys	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNASE1L3	ENST00000394549.7	c.616C>T	p.Arg206Cys	missense_variant	6/8	1	NM_004944.4	P1
DNASE1L3	ENST00000483681.5	c.616C>T	p.Arg206Cys	missense_variant	8/9	5
DNASE1L3	ENST00000486455.5	c.526C>T	p.Arg176Cys	missense_variant	5/7	2
DNASE1L3	ENST00000477209.5	c.238C>T	p.Arg80Cys	missense_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.0461 AC: 7016 AN: 152182 Hom.: 213 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0276

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0756

Gnomad OTH AF: 0.0358

GnomAD3 exomes AF: 0.0483 AC: 12137 AN: 251140 Hom.: 411 AF XY: 0.0497 AC XY: 6747 AN XY: 135708

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0362

Gnomad FIN exome AF: 0.0559

Gnomad NFE exome AF: 0.0730

Gnomad OTH exome AF: 0.0529

GnomAD4 exome AF: 0.0681 AC: 99615 AN: 1461764 Hom.: 3797 Cov.: 31 AF XY: 0.0674 AC XY: 48981 AN XY: 727158

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.0225

Gnomad4 ASJ exome AF: 0.0269

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0355

Gnomad4 FIN exome AF: 0.0575

Gnomad4 NFE exome AF: 0.0790

Gnomad4 OTH exome AF: 0.0570

GnomAD4 genome AF: 0.0461 AC: 7017 AN: 152300 Hom.: 213 Cov.: 32 AF XY: 0.0448 AC XY: 3334 AN XY: 74470

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.0300

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.0574

Gnomad4 NFE AF: 0.0757

Gnomad4 OTH AF: 0.0354

Alfa AF: 0.0672 Hom.: 649

Bravo AF: 0.0427

TwinsUK AF: 0.0906 AC: 336

ALSPAC AF: 0.0763 AC: 294

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.0751 AC: 646

ExAC AF: 0.0484 AC: 5876

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0678

EpiControl AF: 0.0710

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	.;.;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D
MetaRNN	Benign	0.022	T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.7	.;.;.;H
MutationTaster	Benign	2.3e-9	P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.7	D;D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.63
ClinPred		0.12	T
GERP RS		5.3
Varity_R		0.89
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs35677470; hg19: chr3-58183636; COSMIC: COSV59155111; COSMIC: COSV59155111;