NM_005223.4:c.319A>G

Variant names:

• chr16-3656184-A-G
• rs8176928
• NM_005223.4:c.319A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PP3_Moderate BP6_Moderate BS2

The NM_005223.4(DNASE1):​c.319A>G​(p.Arg107Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000752 in 1,614,018 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (2 hom.)
• Consequence: DNASE1 NM_005223.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.27
• Publications: 9 publications found

Genes affected

DNASE1 (HGNC:2956): (deoxyribonuclease 1) This gene encodes a member of the DNase family. This protein is stored in the zymogen granules of the nuclear envelope and functions by cleaving DNA in an endonucleolytic manner. At least six autosomal codominant alleles have been characterized, DNASE1*1 through DNASE1*6, and the sequence of DNASE1*2 represented in this record. Mutations in this gene have been associated with systemic lupus erythematosus (SLE), an autoimmune disease. A recombinant form of this protein is used to treat the one of the symptoms of cystic fibrosis by hydrolyzing the extracellular DNA in sputum and reducing its viscosity. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

LOC124903631 (HGNC:):

TRAP1 (HGNC:16264): (TNF receptor associated protein 1) This gene encodes a mitochondrial chaperone protein that is member of the heat shock protein 90 (HSP90) family. The encoded protein has ATPase activity and interacts with tumor necrosis factor type I. This protein may function in regulating cellular stress responses. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

TRAP1 Gene-Disease associations (from GenCC):

• syndromic disease

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 16-3656184-A-G is Benign according to our data. Variant chr16-3656184-A-G is described in ClinVar as Benign. ClinVar VariationId is 2646120.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 562 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005223.4. 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
	DNASE1	NM_005223.4	MANE Select	c.319A>G	p.Arg107Gly	missense splice_region	Exon 4 of 9	NP_005214.2
	DNASE1	NM_001387139.1		c.319A>G	p.Arg107Gly	missense splice_region	Exon 4 of 9	NP_001374068.1
	DNASE1	NM_001351825.2		c.319A>G	p.Arg107Gly	missense splice_region	Exon 5 of 10	NP_001338754.1	P24855-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNASE1	ENST00000246949.10	TSL:1 MANE Select	c.319A>G	p.Arg107Gly	missense splice_region	Exon 4 of 9	ENSP00000246949.5	P24855-1
	DNASE1	ENST00000407479.5	TSL:1	c.319A>G	p.Arg107Gly	missense splice_region	Exon 5 of 10	ENSP00000385905.1	P24855-1
	DNASE1	ENST00000570376.5	TSL:3	n.*47A>G		splice_region non_coding_transcript_exon	Exon 3 of 5	ENSP00000461725.1	I3L530

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 562 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00101 AC: 254 AN: 251386 AF XY: 0.000684

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000446 AC: 652 AN: 1461728 Hom.: 2 Cov.: 33 AF XY: 0.000369 AC XY: 268 AN XY: 727184

African (AFR) AF: 0.0147 AC: 491 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111976

Other (OTH) AF: 0.00142 AC: 86 AN: 60394

GnomAD4 genome AF: 0.00369 AC: 562 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74464

African (AFR) AF: 0.0129 AC: 537 AN: 41564

American (AMR) AF: 0.00111 AC: 17 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00135 Hom.: 3

Bravo AF: 0.00405

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.038	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		5.3
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.88
MPC		0.031
ClinPred		0.13	T
GERP RS		5.0
Varity_R		0.95
gMVP		0.86
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8176928; hg19: chr16-3706185;