6-30655255-G-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BS1_SupportingBS2
The NM_003587.5(DHX16):c.2743C>T(p.Arg915Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
DHX16
NM_003587.5 missense
NM_003587.5 missense
Scores
9
5
2
Clinical Significance
Conservation
PhyloP100: 3.15
Genes affected
DHX16 (HGNC:2739): (DEAH-box helicase 16) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is a functional homolog of fission yeast Prp8 protein involved in cell cycle progression. This gene is mapped to the MHC region on chromosome 6p21.3, a region where many malignant, genetic and autoimmune disease genes are linked. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2018]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP2
Missense variant where missense usually causes diseases, DHX16
PP3
MetaRNN computational evidence supports a deleterious effect, 0.817
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000233 (34/1461858) while in subpopulation AMR AF= 0.000112 (5/44724). AF 95% confidence interval is 0.0000436. There are 0 homozygotes in gnomad4_exome. There are 20 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 34 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHX16 | NM_003587.5 | c.2743C>T | p.Arg915Trp | missense_variant | 18/20 | ENST00000376442.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHX16 | ENST00000376442.8 | c.2743C>T | p.Arg915Trp | missense_variant | 18/20 | 1 | NM_003587.5 | P1 | |
DHX16 | ENST00000376437.9 | c.1300C>T | p.Arg434Trp | missense_variant | 10/12 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152128Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251372Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135866
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 727228
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74302
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2023 | The c.2743C>T (p.R915W) alteration is located in exon 18 (coding exon 18) of the DHX16 gene. This alteration results from a C to T substitution at nucleotide position 2743, causing the arginine (R) at amino acid position 915 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
0.57
.;Loss of disorder (P = 0.003);
MVP
MPC
0.62
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at