6-73416152-A-G

Variant names:

• chr6-73416152-A-G
• rs311686
• NM_018665.3:c.1873A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018665.3(DDX43):​c.1873A>G​(p.Lys625Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,561,086 control chromosomes in the GnomAD database, including 232,633 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (18477 hom., cov: 32)
  • Exomes 𝑓: 0.54 (214156 hom.)
• Consequence: DDX43 NM_018665.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59
• Publications: 45 publications found

Genes affected

DDX43 (HGNC:18677): (DEAD-box helicase 43) The protein encoded by this gene is an ATP-dependent RNA helicase in the DEAD-box family and displays tumor-specific expression. [provided by RefSeq, Jul 2008]

CGAS (HGNC:21367): (cyclic GMP-AMP synthase) Enables several functions, including 2',3'-cyclic GMP-AMP synthase activity; chromatin binding activity; and phosphatidylinositol-4,5-bisphosphate binding activity. Involved in several processes, including cellular response to exogenous dsRNA; positive regulation of intracellular signal transduction; and regulation of defense response. Located in several cellular components, including cytosol; nucleus; and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5032355E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX43	NM_018665.3	c.1873A>G	p.Lys625Glu	missense_variant	Exon 16 of 17	ENST00000370336.5	NP_061135.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX43	ENST00000370336.5	c.1873A>G	p.Lys625Glu	missense_variant	Exon 16 of 17	1	NM_018665.3	ENSP00000359361.4
CGAS	ENST00000370318.5	c.1333-2131T>C		intron_variant	Intron 5 of 5	1		ENSP00000359342.1

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73575 AN: 151388 Hom.: 18481 Cov.: 32

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.497

GnomAD2 exomes AF: 0.516 AC: 128864 AN: 249836 AF XY: 0.527

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.543

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.550

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.545 AC: 768200 AN: 1409578 Hom.: 214156 Cov.: 29 AF XY: 0.548 AC XY: 385487 AN XY: 703666

African (AFR) AF: 0.346 AC: 11324 AN: 32698

American (AMR) AF: 0.413 AC: 18357 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11808 AN: 25794

East Asian (EAS) AF: 0.532 AC: 20928 AN: 39332

South Asian (SAS) AF: 0.584 AC: 49517 AN: 84804

European-Finnish (FIN) AF: 0.533 AC: 28359 AN: 53208

Middle Eastern (MID) AF: 0.545 AC: 3103 AN: 5692

European-Non Finnish (NFE) AF: 0.558 AC: 594015 AN: 1064942

Other (OTH) AF: 0.525 AC: 30789 AN: 58622

GnomAD4 genome AF: 0.486 AC: 73596 AN: 151508 Hom.: 18477 Cov.: 32 AF XY: 0.490 AC XY: 36232 AN XY: 73990

African (AFR) AF: 0.355 AC: 14664 AN: 41342

American (AMR) AF: 0.462 AC: 7036 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1626 AN: 3464

East Asian (EAS) AF: 0.539 AC: 2771 AN: 5138

South Asian (SAS) AF: 0.600 AC: 2894 AN: 4822

European-Finnish (FIN) AF: 0.539 AC: 5632 AN: 10450

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37423 AN: 67772

Other (OTH) AF: 0.500 AC: 1053 AN: 2106

Alfa AF: 0.527 Hom.: 67464

Bravo AF: 0.472

TwinsUK AF: 0.566 AC: 2097

ALSPAC AF: 0.579 AC: 2230

ESP6500AA AF: 0.371 AC: 1633

ESP6500EA AF: 0.544 AC: 4677

ExAC AF: 0.517 AC: 62818

Asia WGS AF: 0.531 AC: 1852 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.84
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.000015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.071
Sift	Benign	0.37	T
Sift4G	Benign	0.47	T
Vest4		0.028
ClinPred		0.0074	T
GERP RS		4.1
Varity_R		0.075
gMVP		0.52
Mutation Taster		=99/1	polymorphism (auto)

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: rs311686; hg19: chr6-74125875; COSMIC: COSV64812478; COSMIC: COSV64812478;