chr3-58192805-T-C

Variant names:

• chr3-58192805-T-C
• NM_004944.4:c.802-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004944.4(DNASE1L3):​c.802-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000685 in 1,459,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DNASE1L3 NM_004944.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.01
• Publications: 0 publications found

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]

DNASE1L3 Gene-Disease associations (from GenCC):

• autosomal systemic lupus erythematosus type 16

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• hypocomplementemic urticarial vasculitis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004944.4. 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
	DNASE1L3	NM_004944.4	MANE Select	c.802-2A>G		splice_acceptor intron	N/A	NP_004935.1	Q13609-1
	DNASE1L3	NM_001256560.2		c.712-2A>G		splice_acceptor intron	N/A	NP_001243489.1	Q13609-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE1L3	ENST00000394549.7	TSL:1 MANE Select	c.802-2A>G		splice_acceptor intron	N/A	ENSP00000378053.2	Q13609-1
	DNASE1L3	ENST00000483681.5	TSL:5	c.*472A>G		3_prime_UTR	Exon 9 of 9	ENSP00000417047.1	A0A0A0MT68
	DNASE1L3	ENST00000907344.1		c.829-2A>G		splice_acceptor intron	N/A	ENSP00000577403.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459768 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726072

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111528

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.0
GERP RS		4.8
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -16
DS_AL_spliceai		0.99		Position offset: -2

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

Other links and lift over

hg19: chr3-58178532; COSMIC: COSV100568829;