17-59566786-A-T

Position:

• chr17-59566786-A-T

Variant summary

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

The NM_024612.5(DHX40):​c.272A>T​(p.Tyr91Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHX40 NM_024612.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17852494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX40	NM_024612.5	c.272A>T	p.Tyr91Phe	missense_variant	2/18	ENST00000251241.9	NP_078888.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX40	ENST00000251241.9	c.272A>T	p.Tyr91Phe	missense_variant	2/18	1	NM_024612.5	ENSP00000251241.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Nov 09, 2024

The c.272A>T (p.Y91F) alteration is located in exon 2 (coding exon 2) of the DHX40 gene. This alteration results from a A to T substitution at nucleotide position 272, causing the tyrosine (Y) at amino acid position 91 to be replaced by a phenylalanine (F). 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	0.098
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.11
Sift	Benign	0.44	T;.
Sift4G	Benign	0.37	T;T
Polyphen		0.028	B;.
Vest4		0.23
MutPred		0.39		Loss of ubiquitination at K88 (P = 0.0795);.;
MVP		0.43
MPC		0.85
ClinPred		0.41	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs948789933; hg19: chr17-57644147;