3-58193339-T-C

Position:

• chr3-58193339-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004944.4(DNASE1L3):​c.801+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNASE1L3 NM_004944.4 splice_region, intron
• Scores: Splicing: ADA: 0.5868
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.338

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14602008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNASE1L3	NM_004944.4	c.801+4A>G		splice_region_variant, intron_variant		ENST00000394549.7	NP_004935.1
DNASE1L3	NM_001256560.2	c.711+4A>G		splice_region_variant, intron_variant			NP_001243489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNASE1L3	ENST00000394549.7	c.801+4A>G		splice_region_variant, intron_variant		1	NM_004944.4	ENSP00000378053.2
DNASE1L3	ENST00000483681.5	c.805A>G	p.Arg269Gly	missense_variant	9/9	5		ENSP00000417047.1
DNASE1L3	ENST00000486455.5	c.711+4A>G		splice_region_variant, intron_variant		2		ENSP00000419052.1
DNASE1L3	ENST00000477209.5	c.327-536A>G		intron_variant		2		ENSP00000417976.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with DNASE1L3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 7 of the DNASE1L3 gene. It does not directly change the encoded amino acid sequence of the DNASE1L3 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.97
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.070
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Vest4		0.090
MutPred		0.45		Gain of glycosylation at S272 (P = 0.0401);
MVP		0.44
ClinPred		0.063	T
GERP RS		0.067

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Benign	0.53
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: rs2097395289; hg19: chr3-58179066;