Genetic Variant DDX43:p.Ile466Thr (chr6-73413686-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018665.3(DDX43):c.1397T>C(p.Ile466Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DDX43
NM_018665.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.37

Publications

0 publications found

Variant links:

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]

DDX43 links:

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]

CGAS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018665.3. 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
	DDX43	NM_018665.3	MANE Select	c.1397T>C	p.Ile466Thr	missense	Exon 12 of 17	NP_061135.2	Q9NXZ2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DDX43	ENST00000370336.5	TSL:1 MANE Select	c.1397T>C	p.Ile466Thr	missense	Exon 12 of 17	ENSP00000359361.4	Q9NXZ2-1
CGAS	ENST00000370318.5	TSL:1	c.*324A>G		3_prime_UTR	Exon 6 of 6	ENSP00000359342.1	Q8N884-2
DDX43	ENST00000942801.1		c.1397T>C	p.Ile466Thr	missense	Exon 12 of 16	ENSP00000612860.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251158

AF XY:

0.00000737

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111866

Other (OTH)

AF:

0.0000663

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

Eigen

Benign

0.10

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.2

PhyloP100

6.4

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.21

Sift

Benign

0.15

Sift4G

Benign

0.38

Polyphen

0.79

Vest4

0.38

MutPred

0.66

Loss of stability (P = 0.0107)

MVP

0.66

MPC

0.54

ClinPred

0.72

GERP RS

4.8

Varity_R

0.33

gMVP

0.35

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over