Variant 17-59573936-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_024612.5(DHX40):c.743G>A(p.Arg248Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000016 in 1,438,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DHX40
NM_024612.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.07

Variant links:

Genes affected

DHX40 (HGNC:18018): (DEAH-box helicase 40) This gene encodes a member of the DExH/D box family of ATP-dependent RNA helicases that have an essential role in RNA metabolism. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 17.[provided by RefSeq, Oct 2009]

DHX40 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.115741104).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX40	NM_024612.5 linkuse as main transcript	c.743G>A	p.Arg248Gln	missense_variant	5/18	ENST00000251241.9	NP_078888.4	Q8IX18-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX40	ENST00000251241.9 linkuse as main transcript	c.743G>A	p.Arg248Gln	missense_variant	5/18	1	NM_024612.5	ENSP00000251241.4		Q8IX18-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143356

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000232

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000385

AC:

AN:

233626

Hom.:

AF XY:

0.0000471

AC XY:

AN XY:

127340

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000274

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000160

AC:

AN:

1438466

Hom.:

Cov.:

AF XY:

0.0000224

AC XY:

AN XY:

715158

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.0000230

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000224

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.14e-7

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000698

AC:

AN:

143356

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

69332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000232

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.743G>A (p.R248Q) alteration is located in exon 5 (coding exon 5) of the DHX40 gene. This alteration results from a G to A substitution at nucleotide position 743, causing the arginine (R) at amino acid position 248 to be replaced by a glutamine (Q). 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

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

T;.;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0089

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.66

N;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.8

N;.;.

REVEL

Benign

0.13

Sift

Benign

0.31

T;.;.

Sift4G

Benign

0.14

T;T;T

Polyphen

0.80

P;.;.

Vest4

0.26

MutPred

0.44

Loss of sheet (P = 0.0817);.;.;

MVP

0.31

MPC

1.0

ClinPred

0.14

GERP RS

4.4

Varity_R

0.085

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over