6-30659612-C-T

Variant names:

• chr6-30659612-C-T
• NM_003587.5:c.1867G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003587.5(DHX16):​c.1867G>A​(p.Ala623Thr) 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. 15/22 in silico tools predict a benign 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: 0.456
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05173391).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHX16	NM_003587.5	c.1867G>A	p.Ala623Thr	missense_variant	Exon 12 of 20	ENST00000376442.8	NP_003578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHX16	ENST00000376442.8	c.1867G>A	p.Ala623Thr	missense_variant	Exon 12 of 20	1	NM_003587.5	ENSP00000365625.3
DHX16	ENST00000376437.9	c.424G>A	p.Ala142Thr	missense_variant	Exon 4 of 12	1		ENSP00000365620.5
DHX16	ENST00000480966.1	n.658G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1867G>A (p.A623T) alteration is located in exon 12 (coding exon 12) of the DHX16 gene. This alteration results from a G to A substitution at nucleotide position 1867, causing the alanine (A) at amino acid position 623 to be replaced by a threonine (T). 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	0.078
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Benign	0.42
DEOGEN2	Benign	0.071	.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	.;N
PhyloP100		0.46
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	2.3	N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.32
MutPred		0.27		.;Gain of phosphorylation at A623 (P = 0.1418);
MVP		0.33
MPC		0.58
ClinPred		0.76	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.13
gMVP		0.45
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

hg19: chr6-30627389;