6-73400354-T-G

Position:

• chr6-73400354-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018665.3(DDX43):​c.427T>G​(p.Cys143Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 1,453,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: DDX43 NM_018665.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.581

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07637277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX43	NM_018665.3	c.427T>G	p.Cys143Gly	missense_variant	3/17	ENST00000370336.5	NP_061135.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX43	ENST00000370336.5	c.427T>G	p.Cys143Gly	missense_variant	3/17	1	NM_018665.3	ENSP00000359361.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000895 AC: 13 AN: 1453046 Hom.: 0 Cov.: 30 AF XY: 0.00000830 AC XY: 6 AN XY: 722464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The c.427T>G (p.C143G) alteration is located in exon 3 (coding exon 3) of the DDX43 gene. This alteration results from a T to G substitution at nucleotide position 427, causing the cysteine (C) at amino acid position 143 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.2
DANN	Benign	0.44
DEOGEN2	Benign	0.00025	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.60	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.021
Sift	Benign	0.49	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.49		Gain of disorder (P = 0.0051);
MVP		0.12
MPC		0.41
ClinPred		0.031	T
GERP RS		-6.4
Varity_R		0.049
gMVP		0.061

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: rs776408319; hg19: chr6-74110077;