6-30655493-C-G

Variant names:

• chr6-30655493-C-G
• rs188444038
• NM_003587.5:c.2603G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003587.5(DHX16):​c.2603G>C​(p.Arg868Pro) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R868H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHX16 NM_003587.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• Publications: 1 publications found

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]

DHX16 Gene-Disease associations (from GenCC):

• neuromuscular disease and ocular or auditory anomalies with or without seizures

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003587.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX16	NM_003587.5	MANE Select	c.2603G>C	p.Arg868Pro	missense	Exon 17 of 20	NP_003578.2	O60231
	DHX16	NM_001164239.2		c.2423G>C	p.Arg808Pro	missense	Exon 17 of 20	NP_001157711.1	A0A1U9X7L7
	DHX16	NM_001363515.2		c.1160G>C	p.Arg387Pro	missense	Exon 18 of 21	NP_001350444.1	Q5SQH5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX16	ENST00000376442.8	TSL:1 MANE Select	c.2603G>C	p.Arg868Pro	missense	Exon 17 of 20	ENSP00000365625.3	O60231
	DHX16	ENST00000376437.9	TSL:1	c.1160G>C	p.Arg387Pro	missense	Exon 9 of 12	ENSP00000365620.5	Q5SQH5
	DHX16	ENST00000934642.1		c.2624G>C	p.Arg875Pro	missense	Exon 17 of 20	ENSP00000604701.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	4.2	H
PhyloP100		2.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.67		Loss of catalytic residue at R868 (P = 0.0101)
MVP		0.75
MPC		0.86
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.79
gMVP		0.92
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs188444038; hg19: chr6-30623270;