17-59573839-G-A

Position:

• chr17-59573839-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_024612.5(DHX40):​c.646G>A​(p.Ala216Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,552 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: not found (cov: 29)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: DHX40 NM_024612.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2354531).
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX40	NM_024612.5	c.646G>A	p.Ala216Thr	missense_variant	5/18	ENST00000251241.9	NP_078888.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX40	ENST00000251241.9	c.646G>A	p.Ala216Thr	missense_variant	5/18	1	NM_024612.5	ENSP00000251241.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461552 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727088

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: 0.0000216

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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 30, 2024

The c.646G>A (p.A216T) 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 646, causing the alanine (A) at amino acid position 216 to be replaced by a threonine (T). 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	0.074
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T;.;T;T
Eigen	Benign	0.092
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.39	N;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.94	N;.;.;.
REVEL	Benign	0.046
Sift	Benign	0.18	T;.;.;.
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.037	B;.;.;.
Vest4		0.18
MutPred		0.25		Loss of helix (P = 0.0626);.;.;.;
MVP		0.24
MPC		0.93
ClinPred		0.56	D
GERP RS		5.6
Varity_R		0.12
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-57651200;