dbSNP rs760095531: DNASE1L2:p.Val177Met (chr16-2237587-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.70

Variant links:

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]

DNASE1L2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
DNASE1L2	NM_001374.3 link	c.529G>A	p.Val177Met	missense_variant	Exon 5 of 7	ENST00000320700.10	NP_001365.1	Q92874-1
DNASE1L2	NM_001301680.2 link	c.529G>A	p.Val177Met	missense_variant	Exon 5 of 7		NP_001288609.1	Q92874-1
DNASE1L2	XM_047433684.1 link	c.529G>A	p.Val177Met	missense_variant	Exon 4 of 6		XP_047289640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNASE1L2	ENST00000320700.10 link	c.529G>A	p.Val177Met	missense_variant	Exon 5 of 7	1	NM_001374.3	ENSP00000316938.5		Q92874-1

Frequencies

GnomAD3 genomes

AF:

0.00000680

AC:

AN:

147064

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00000412

AC:

AN:

242574

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133248

show subpopulations

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 SAS 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:

AN:

1432438

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712480

show subpopulations

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:

0.00

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.00000680

AC:

AN:

147064

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71658

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000833

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.0083

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.;D;D;.;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.88

.;D;.;D;.;D

M_CAP

Uncertain

0.095

MetaRNN

Uncertain

0.60

D;D;D;D;D;D

MetaSVM

Uncertain

0.071

MutationAssessor

Uncertain

2.5

M;.;M;M;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.5

N;.;N;N;N;N

REVEL

Uncertain

0.49

Sift

Benign

0.061

T;.;T;T;T;T

Sift4G

Benign

0.072

T;T;T;T;T;D

Polyphen

1.0

D;.;D;D;.;.

Vest4

0.26

MutPred

0.55

Gain of disorder (P = 0.1327);.;Gain of disorder (P = 0.1327);Gain of disorder (P = 0.1327);.;.;

MVP

0.78

MPC

0.81

ClinPred

0.90

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over