chr3-58192702-C-G

Position:

• chr3-58192702-C-G

Variant summary

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

The NM_004944.4(DNASE1L3):​c.903G>C​(p.Lys301Asn) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNASE1L3 NM_004944.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0660

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=0.097923696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNASE1L3	NM_004944.4	c.903G>C	p.Lys301Asn	missense_variant	8/8	ENST00000394549.7	NP_004935.1
DNASE1L3	NM_001256560.2	c.813G>C	p.Lys271Asn	missense_variant	7/7		NP_001243489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNASE1L3	ENST00000394549.7	c.903G>C	p.Lys301Asn	missense_variant	8/8	1	NM_004944.4	ENSP00000378053.2
DNASE1L3	ENST00000486455.5	c.813G>C	p.Lys271Asn	missense_variant	7/7	2		ENSP00000419052.1
DNASE1L3	ENST00000483681	c.*575G>C		3_prime_UTR_variant	9/9	5		ENSP00000417047.1
DNASE1L3	ENST00000477209	c.*14G>C		3_prime_UTR_variant	4/4	2		ENSP00000417976.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Mar 23, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1969371). 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 replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 301 of the DNASE1L3 protein (p.Lys301Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0029	.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.70	N;N
REVEL	Benign	0.028
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.011	.;B
Vest4		0.17
MutPred		0.19		.;Gain of glycosylation at S302 (P = 8e-04);
MVP		0.41
ClinPred		0.073	T
GERP RS		3.0
Varity_R		0.056
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-58178429;