6-73416152-A-G

Position:

• chr6-73416152-A-G

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
DDX43	NM_018665.3	c.1873A>G	p.Lys625Glu	missense_variant	16/17	ENST00000370336.5	NP_061135.2

Ensembl

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

GnomAD3 exomes AF: 0.516 AC: 128864 AN: 249836 Hom.: 34056 AF XY: 0.527 AC XY: 71241 AN XY: 135092

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 SAS exome AF: 0.586

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

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.413

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.532

Gnomad4 SAS exome AF: 0.584

Gnomad4 FIN exome AF: 0.533

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.525

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

Gnomad4 AFR AF: 0.355

Gnomad4 AMR AF: 0.462

Gnomad4 ASJ AF: 0.469

Gnomad4 EAS AF: 0.539

Gnomad4 SAS AF: 0.600

Gnomad4 FIN AF: 0.539

Gnomad4 NFE AF: 0.552

Gnomad4 OTH AF: 0.500

Alfa AF: 0.538 Hom.: 50467

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
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.071
Sift	Benign	0.37	T
Sift4G	Benign	0.47	T
Polyphen		0.0020	B
Vest4		0.028
MPC		0.47
ClinPred		0.0074	T
GERP RS		4.1
Varity_R		0.075
gMVP		0.52

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

Other links and lift over

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