rs886037652

Variant names:

• chr1-200644514-C-T
• rs886037652
• NM_001031725.6:c.1600G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001031725.6(DDX59):​c.1600G>A​(p.Gly534Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,411,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DDX59 NM_001031725.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.66
• Publications: 5 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

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.1600G>A	p.Gly534Arg	missense	Exon 8 of 8	NP_001026895.2	Q5T1V6-1
	DDX59	NM_001349799.3		c.1600G>A	p.Gly534Arg	missense	Exon 8 of 8	NP_001336728.1	Q5T1V6-1
	DDX59	NM_001349800.3		c.1600G>A	p.Gly534Arg	missense	Exon 8 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.1600G>A	p.Gly534Arg	missense	Exon 8 of 8	ENSP00000330460.6	Q5T1V6-1
	DDX59	ENST00000936161.1		c.1600G>A	p.Gly534Arg	missense	Exon 7 of 7	ENSP00000606220.1
	DDX59	ENST00000936162.1		c.1600G>A	p.Gly534Arg	missense	Exon 8 of 8	ENSP00000606221.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1411154 Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2 AN XY: 699496

African (AFR) AF: 0.00 AC: 0 AN: 30932

American (AMR) AF: 0.00 AC: 0 AN: 34738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24026

East Asian (EAS) AF: 0.00 AC: 0 AN: 38136

South Asian (SAS) AF: 0.00 AC: 0 AN: 78284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5528

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1089194

Other (OTH) AF: 0.00 AC: 0 AN: 58128

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Orofaciodigital syndrome V (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		7.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.97		Gain of MoRF binding (P = 0.0149)
MVP		0.99
MPC		0.77
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.90
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs886037652; hg19: chr1-200613642; COSMIC: COSV58753683;