6-30656699-G-T

Position:

• chr6-30656699-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003587.5(DHX16):​c.2209C>A​(p.Leu737Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHX16 NM_003587.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DHX16. . Gene score misZ 3.0787 (greater than the threshold 3.09). Trascript score misZ 4.2489 (greater than threshold 3.09). GenCC has associacion of gene with neuromuscular disease and ocular or auditory anomalies with or without seizures.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX16	NM_003587.5	c.2209C>A	p.Leu737Met	missense_variant	14/20	ENST00000376442.8	NP_003578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX16	ENST00000376442.8	c.2209C>A	p.Leu737Met	missense_variant	14/20	1	NM_003587.5	ENSP00000365625.3
DHX16	ENST00000376437.9	c.766C>A	p.Leu256Met	missense_variant	6/12	1		ENSP00000365620.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.2209C>A (p.L737M) alteration is located in exon 14 (coding exon 14) of the DHX16 gene. This alteration results from a C to A substitution at nucleotide position 2209, causing the leucine (L) at amino acid position 737 to be replaced by a methionine (M). 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	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.76
MVP		0.58
MPC		0.58
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.30
gMVP		0.82

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

Other links and lift over

dbSNP: rs1469755408; hg19: chr6-30624476;