16-2237587-G-A

Variant names:

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

Variant summary

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

The NM_001374.3(DNASE1L2):​c.529G>A​(p.Val177Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,579,502 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V177L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DNASE1L2 NM_001374.3 missense
• Clinical Significance: Not reported in ClinVar
• 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>A	p.Val177Met	missense	Exon 5 of 7	NP_001365.1	Q92874-1
	DNASE1L2	NM_001301680.2		c.529G>A	p.Val177Met	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>A	p.Val177Met	missense	Exon 5 of 7	ENSP00000316938.5	Q92874-1
	DNASE1L2	ENST00000564065.5	TSL:1	c.529G>A	p.Val177Met	missense	Exon 4 of 6	ENSP00000454562.1	Q92874-1
	DNASE1L2	ENST00000567494.5	TSL:1	c.529G>A	p.Val177Met	missense	Exon 5 of 7	ENSP00000455358.1	Q92874-1

Frequencies

GnomAD3 genomes AF: 0.00000680 AC: 1 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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242574 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432438 Hom.: 0 Cov.: 38 AF XY: 0.00000140 AC XY: 1 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: 0.00 AC: 0 AN: 1093546

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

GnomAD4 genome AF: 0.00000680 AC: 1 AN: 147064 Hom.: 0 Cov.: 33 AF XY: 0.0000140 AC XY: 1 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: 0.0000149 AC: 1 AN: 66912

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000833 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.0083	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.071	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.49
Sift	Benign	0.061	T
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.26
MutPred		0.55		Gain of disorder (P = 0.1327)
MVP		0.78
MPC		0.81
ClinPred		0.90	D
GERP RS		4.3
Varity_R		0.14
gMVP		0.76

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;