chr16-2237938-G-A

Variant names:

• chr16-2237938-G-A
• rs773366458
• NM_001374.3:c.763G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001374.3(DNASE1L2):​c.763G>A​(p.Ala255Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,602,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: DNASE1L2 NM_001374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.414
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05401036).

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.763G>A	p.Ala255Thr	missense	Exon 6 of 7	NP_001365.1	Q92874-1
	DNASE1L2	NM_001301680.2		c.763G>A	p.Ala255Thr	missense	Exon 6 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.763G>A	p.Ala255Thr	missense	Exon 6 of 7	ENSP00000316938.5	Q92874-1
	DNASE1L2	ENST00000564065.5	TSL:1	c.763G>A	p.Ala255Thr	missense	Exon 5 of 6	ENSP00000454562.1	Q92874-1
	DNASE1L2	ENST00000567494.5	TSL:1	c.763G>A	p.Ala255Thr	missense	Exon 6 of 7	ENSP00000455358.1	Q92874-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000620 AC: 14 AN: 225794 AF XY: 0.0000561

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000339

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.0000179 AC: 26 AN: 1450086 Hom.: 0 Cov.: 37 AF XY: 0.0000180 AC XY: 13 AN XY: 721130

African (AFR) AF: 0.00 AC: 0 AN: 33058

American (AMR) AF: 0.000232 AC: 10 AN: 43022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 38518

South Asian (SAS) AF: 0.00 AC: 0 AN: 85358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5376

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1108658

Other (OTH) AF: 0.00 AC: 0 AN: 59828

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000168 AC: 2

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	0.079
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.41
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.017
Sift	Benign	0.55	T
Sift4G	Benign	0.47	T
Polyphen		0.32	B
Vest4		0.17
MutPred		0.28		Loss of methylation at R256 (P = 0.0782)
MVP		0.19
MPC		0.24
ClinPred		0.022	T
GERP RS		2.3
Varity_R		0.043
gMVP		0.57
Mutation Taster		=93/7	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: rs773366458; hg19: chr16-2287939; COSMIC: COSV108828339; COSMIC: COSV108828339;