1-200650639-A-C

Variant names:

• chr1-200650639-A-C
• rs587777067
• NM_001031725.6:c.1100T>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000515932: Functional studies show that V367G results in decreased expression of the DDX59 protein as well as impaired SHH signaling in SAG-treated fibroblasts (Shamseldin et al., 2013).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDX59 NM_001031725.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.26
• Publications: 3 publications found

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]

DDX59 Gene-Disease associations (from GenCC):

• orofaciodigital syndrome V

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000515932: Functional studies show that V367G results in decreased expression of the DDX59 protein as well as impaired SHH signaling in SAG-treated fibroblasts (Shamseldin et al., 2013).
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 88653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031725.6. 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
	DDX59	NM_001031725.6	MANE Select	c.1100T>G	p.Val367Gly	missense	Exon 5 of 8	NP_001026895.2	Q5T1V6-1
	DDX59	NM_001349799.3		c.1100T>G	p.Val367Gly	missense	Exon 5 of 8	NP_001336728.1	Q5T1V6-1
	DDX59	NM_001349800.3		c.1100T>G	p.Val367Gly	missense	Exon 5 of 8	NP_001336729.1	Q5T1V6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX59	ENST00000331314.11	TSL:1 MANE Select	c.1100T>G	p.Val367Gly	missense	Exon 5 of 8	ENSP00000330460.6	Q5T1V6-1
	DDX59	ENST00000936161.1		c.1100T>G	p.Val367Gly	missense	Exon 4 of 7	ENSP00000606220.1
	DDX59	ENST00000936162.1		c.1100T>G	p.Val367Gly	missense	Exon 5 of 8	ENSP00000606221.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Orofaciodigital syndrome V (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.012	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.84		Loss of stability (P = 0.0334)
MVP		0.93
MPC		0.82
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		0.011	Neutral
Varity_R		0.99
gMVP		0.80
Mutation Taster		=1/99	disease causing (ClinVar)

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

dbSNP: rs587777067; hg19: chr1-200619767;