16-2237587-G-T

Variant names:

• chr16-2237587-G-T
• rs760095531
• NM_001374.3:c.529G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001374.3(DNASE1L2):​c.529G>T​(p.Val177Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000095 in 1,579,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: DNASE1L2 NM_001374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70
• Publications: 3 publications found

Genes affected

DNASE1L2 (HGNC:2958): (deoxyribonuclease 1 like 2) Predicted to enable DNA binding activity and deoxyribonuclease I activity. Predicted to be involved in DNA catabolic process, endonucleolytic. Predicted to act upstream of or within corneocyte development and hair follicle development. Predicted to be located in cytoplasm and extracellular region. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374.3. 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
	DNASE1L2	NM_001374.3	MANE Select	c.529G>T	p.Val177Leu	missense	Exon 5 of 7	NP_001365.1	Q92874-1
	DNASE1L2	NM_001301680.2		c.529G>T	p.Val177Leu	missense	Exon 5 of 7	NP_001288609.1	Q92874-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE1L2	ENST00000320700.10	TSL:1 MANE Select	c.529G>T	p.Val177Leu	missense	Exon 5 of 7	ENSP00000316938.5	Q92874-1
	DNASE1L2	ENST00000564065.5	TSL:1	c.529G>T	p.Val177Leu	missense	Exon 4 of 6	ENSP00000454562.1	Q92874-1
	DNASE1L2	ENST00000567494.5	TSL:1	c.529G>T	p.Val177Leu	missense	Exon 5 of 7	ENSP00000455358.1	Q92874-1

Frequencies

GnomAD3 genomes AF: 0.0000204 AC: 3 AN: 147064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000448

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000838 AC: 12 AN: 1432438 Hom.: 0 Cov.: 38 AF XY: 0.0000112 AC XY: 8 AN XY: 712480

African (AFR) AF: 0.00 AC: 0 AN: 32532

American (AMR) AF: 0.00 AC: 0 AN: 43710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24944

East Asian (EAS) AF: 0.00 AC: 0 AN: 37952

South Asian (SAS) AF: 0.00 AC: 0 AN: 85862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1093546

Other (OTH) AF: 0.0000171 AC: 1 AN: 58342

GnomAD4 genome AF: 0.0000204 AC: 3 AN: 147064 Hom.: 0 Cov.: 33 AF XY: 0.0000419 AC XY: 3 AN XY: 71658

African (AFR) AF: 0.00 AC: 0 AN: 40182

American (AMR) AF: 0.00 AC: 0 AN: 14648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3416

East Asian (EAS) AF: 0.00 AC: 0 AN: 4556

South Asian (SAS) AF: 0.00 AC: 0 AN: 4318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000448 AC: 3 AN: 66912

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.51
Sift	Benign	0.030	D
Sift4G	Uncertain	0.060	T
Polyphen		0.98	D
Vest4		0.45
MutPred		0.57		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.74
MPC		0.57
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.24
gMVP		0.78
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs760095531; hg19: chr16-2287588; COSMIC: COSV57038929; COSMIC: COSV57038929;