1-200650639-A-C

Position:

• chr1-200650639-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001031725.6(DDX59):​c.1100T>G​(p.Val367Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDX59 NM_001031725.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.26

Genes affected

DDX59 (HGNC:25360): (DEAD-box helicase 59) Predicted to enable RNA binding activity and RNA helicase activity. Predicted to be located in cytoplasm and nucleus. Predicted to be integral component of membrane. Implicated in orofaciodigital syndrome V. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 1-200650639-A-C is Pathogenic according to our data. Variant chr1-200650639-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX59	NM_001031725.6	c.1100T>G	p.Val367Gly	missense_variant	5/8	ENST00000331314.11	NP_001026895.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX59	ENST00000331314.11	c.1100T>G	p.Val367Gly	missense_variant	5/8	1	NM_001031725.6	ENSP00000330460.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orofaciodigital syndrome V Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 05, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Oct 11, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2015

The V367G variant in the DDX59 gene has been reported previously in association with orofaciodigitalsyndrome V (Shamseldin et al., 2013). The V367G substitution was observed in the homozygous state inmultiple affected members of a consanguineous multiplex Arab family with orofaciodigital syndrome. Thisvariant was absent from 300 ethnically matched exome cases evaluated by the authors and was alsoabsent in 200 ethnically matched control individuals by direct DDX59 sequencing (Shamseldin et al., 2013).In addition, the V367G variant was not observed in approximately 6,500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. The V367G variant is a conservative amino acid substitution, which occursat a position that is conserved across species. Functional studies show that V367G results in decreasedexpression of the DDX59 protein as well as impaired SHH signaling in SAG-treated fibroblasts (Shamseldin et al., 2013). We interpret V367G as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	.;.;T;T;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;D;T;T;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.012	D
MutationAssessor	Pathogenic	3.5	M;.;M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.2	D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.88
MutPred		0.84		Loss of stability (P = 0.0334);.;Loss of stability (P = 0.0334);.;.;
MVP		0.93
MPC		0.82
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.80

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: rs587777067; hg19: chr1-200619767;