3-58192745-A-G

Position:

• chr3-58192745-A-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.860T>C​(p.Phe287Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNASE1L3 NM_004944.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.810

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=0.13548866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNASE1L3	NM_004944.4	c.860T>C	p.Phe287Ser	missense_variant	8/8	ENST00000394549.7	NP_004935.1
DNASE1L3	NM_001256560.2	c.770T>C	p.Phe257Ser	missense_variant	7/7		NP_001243489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNASE1L3	ENST00000394549.7	c.860T>C	p.Phe287Ser	missense_variant	8/8	1	NM_004944.4	ENSP00000378053.2
DNASE1L3	ENST00000486455.5	c.770T>C	p.Phe257Ser	missense_variant	7/7	2		ENSP00000419052.1
DNASE1L3	ENST00000477209.5	c.385T>C	p.Ser129Pro	missense_variant	4/4	2		ENSP00000417976.1
DNASE1L3	ENST00000483681	c.*532T>C		3_prime_UTR_variant	9/9	5		ENSP00000417047.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Jun 15, 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 287 of the DNASE1L3 protein (p.Phe287Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.0056	.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.97	.;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.018
Sift	Benign	0.19	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0030	.;B
Vest4		0.12
MutPred		0.25		.;Gain of glycosylation at T288 (P = 0.0072);
MVP		0.42
ClinPred		0.17	T
GERP RS		3.7
Varity_R		0.088
gMVP		0.67

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: rs970045878; hg19: chr3-58178472;