6-30656464-T-C

Position:

• chr6-30656464-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_003587.5(DHX16):​c.2357A>G​(p.Tyr786Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,614,060 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (98 hom.)
• Consequence: DHX16 NM_003587.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.93

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 Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DHX16
• BP4: Computational evidence support a benign effect (MetaRNN=0.0042455494).
• BP6: Variant 6-30656464-T-C is Benign according to our data. Variant chr6-30656464-T-C is described in ClinVar as [Benign]. Clinvar id is 3056890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0019 (289/152174) while in subpopulation SAS AF= 0.042 (202/4814). AF 95% confidence interval is 0.0372. There are 5 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHX16	NM_003587.5	c.2357A>G	p.Tyr786Cys	missense_variant	15/20	ENST00000376442.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHX16	ENST00000376442.8	c.2357A>G	p.Tyr786Cys	missense_variant	15/20	1	NM_003587.5	P1
DHX16	ENST00000376437.9	c.914A>G	p.Tyr305Cys	missense_variant	7/12	1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152056 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0419

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00563 AC: 1415 AN: 251450 Hom.: 37 AF XY: 0.00781 AC XY: 1062 AN XY: 135896

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0410

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00339 AC: 4960 AN: 1461886 Hom.: 98 Cov.: 33 AF XY: 0.00461 AC XY: 3354 AN XY: 727246

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0408

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152174 Hom.: 5 Cov.: 32 AF XY: 0.00277 AC XY: 206 AN XY: 74398

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0420

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000876

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00624 AC: 758

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DHX16-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	0.98
Eigen	Benign	0.043
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.80	D
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.11
Sift	Benign	0.16	T;T
Sift4G	Uncertain	0.040	D;T
Polyphen		0.81	P;P
Vest4		0.44
MVP		0.48
MPC		0.75
ClinPred		0.025	T
GERP RS		5.1
Varity_R		0.24
gMVP		0.75

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: rs149087216; hg19: chr6-30624241; COSMIC: COSV53315041; COSMIC: COSV53315041;