3-58193344-T-C

Position:

• chr3-58193344-T-C

Variant summary

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

The NM_004944.4(DNASE1L3):​c.800A>G​(p.Glu267Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNASE1L3 NM_004944.4 missense, splice_region
• Scores: Splicing: ADA: 0.9978
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNASE1L3	NM_004944.4	c.800A>G	p.Glu267Gly	missense_variant, splice_region_variant	7/8	ENST00000394549.7	NP_004935.1
DNASE1L3	NM_001256560.2	c.710A>G	p.Glu237Gly	missense_variant, splice_region_variant	6/7		NP_001243489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNASE1L3	ENST00000394549.7	c.800A>G	p.Glu267Gly	missense_variant, splice_region_variant	7/8	1	NM_004944.4	ENSP00000378053.2
DNASE1L3	ENST00000483681.5	c.800A>G	p.Glu267Gly	missense_variant	9/9	5		ENSP00000417047.1
DNASE1L3	ENST00000486455.5	c.710A>G	p.Glu237Gly	missense_variant, splice_region_variant	6/7	2		ENSP00000419052.1
DNASE1L3	ENST00000477209.5	c.327-541A>G		intron_variant		2		ENSP00000417976.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Nov 04, 2021

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 267 of the DNASE1L3 protein (p.Glu267Gly). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;.;D
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;T;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.9	.;.;M
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.13
Sift	Benign	0.16	T;D;T
Sift4G	Benign	0.18	T;D;T
Polyphen		0.38	.;.;B
Vest4		0.29
MutPred		0.51		.;Gain of glycosylation at S272 (P = 0.032);Gain of glycosylation at S272 (P = 0.032);
MVP		0.75
ClinPred		0.58	D
GERP RS		4.5
Varity_R		0.29
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-58179071;