17-59598818-C-G

Position:

• chr17-59598818-C-G

Variant summary

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

The NM_024612.5(DHX40):​c.1664C>G​(p.Thr555Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: DHX40 NM_024612.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX40	NM_024612.5	c.1664C>G	p.Thr555Ser	missense_variant	13/18	ENST00000251241.9	NP_078888.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX40	ENST00000251241.9	c.1664C>G	p.Thr555Ser	missense_variant	13/18	1	NM_024612.5	ENSP00000251241.4
DHX40	ENST00000425628.7	c.1433C>G	p.Thr478Ser	missense_variant	12/17	2		ENSP00000388749.3
DHX40	ENST00000538926.2	c.608C>G	p.Thr203Ser	missense_variant	5/6	3		ENSP00000437958.2
DHX40	ENST00000583439.1	n.215C>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 10

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

Mar 11, 2022

The c.1664C>G (p.T555S) alteration is located in exon 13 (coding exon 13) of the DHX40 gene. This alteration results from a C to G substitution at nucleotide position 1664, causing the threonine (T) at amino acid position 555 to be replaced by a serine (S). 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	0.27
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Benign	0.85
DEOGEN2	Benign	0.34	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Benign	0.21
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.047	D;D
Polyphen		0.97	D;.
Vest4		0.49
MutPred		0.66		Gain of helix (P = 0.132);.;
MVP		0.55
MPC		2.8
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.38
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-57676179;