rs3795634

Variant names:

• chr1-200666422-T-C
• rs3795634
• NM_001031725.6:c.319A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001031725.6(DDX59):​c.319A>G​(p.Ile107Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0849 in 1,614,044 control chromosomes in the GnomAD database, including 10,390 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1549 hom., cov: 32)
  • Exomes 𝑓: 0.081 (8841 hom.)
• Consequence: DDX59 NM_001031725.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.75
• Publications: 22 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046088994).
• BP6: Variant 1-200666422-T-C is Benign according to our data. Variant chr1-200666422-T-C is described in ClinVar as Benign. ClinVar VariationId is 1530753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX59	NM_001031725.6	c.319A>G	p.Ile107Val	missense_variant	Exon 2 of 8	ENST00000331314.11	NP_001026895.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX59	ENST00000331314.11	c.319A>G	p.Ile107Val	missense_variant	Exon 2 of 8	1	NM_001031725.6	ENSP00000330460.6
DDX59	ENST00000447706.6	c.319A>G	p.Ile107Val	missense_variant	Exon 2 of 8	2		ENSP00000394367.2
DDX59	ENST00000436897.1	c.319A>G	p.Ile107Val	missense_variant	Exon 2 of 2	3		ENSP00000391312.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17996 AN: 152060 Hom.: 1547 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0535

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.136 AC: 34204 AN: 251350 AF XY: 0.129

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.409

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.0550

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0815 AC: 119085 AN: 1461866 Hom.: 8841 Cov.: 31 AF XY: 0.0828 AC XY: 60209 AN XY: 727232

African (AFR) AF: 0.150 AC: 5030 AN: 33478

American (AMR) AF: 0.247 AC: 11053 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3047 AN: 26136

East Asian (EAS) AF: 0.401 AC: 15903 AN: 39696

South Asian (SAS) AF: 0.160 AC: 13761 AN: 86258

European-Finnish (FIN) AF: 0.120 AC: 6407 AN: 53420

Middle Eastern (MID) AF: 0.114 AC: 655 AN: 5768

European-Non Finnish (NFE) AF: 0.0515 AC: 57245 AN: 1112006

Other (OTH) AF: 0.0991 AC: 5984 AN: 60396

GnomAD4 genome AF: 0.118 AC: 18020 AN: 152178 Hom.: 1549 Cov.: 32 AF XY: 0.126 AC XY: 9386 AN XY: 74384

African (AFR) AF: 0.151 AC: 6269 AN: 41512

American (AMR) AF: 0.195 AC: 2987 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 373 AN: 3466

East Asian (EAS) AF: 0.413 AC: 2129 AN: 5158

South Asian (SAS) AF: 0.177 AC: 851 AN: 4816

European-Finnish (FIN) AF: 0.129 AC: 1366 AN: 10602

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0534 AC: 3635 AN: 68022

Other (OTH) AF: 0.121 AC: 256 AN: 2112

Alfa AF: 0.0782 Hom.: 1953

Bravo AF: 0.125

TwinsUK AF: 0.0591 AC: 219

ALSPAC AF: 0.0542 AC: 209

ESP6500AA AF: 0.145 AC: 639

ESP6500EA AF: 0.0622 AC: 535

ExAC AF: 0.129 AC: 15688

Asia WGS AF: 0.275 AC: 954 AN: 3478

EpiCase AF: 0.0565

EpiControl AF: 0.0557

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.4
DANN	Benign	0.79
DEOGEN2	Benign	0.0033	.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.46	T;T;T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.8	N;N;.
PhyloP100		2.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.62	N;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	.;B;.
Vest4		0.017
MPC		0.14
ClinPred		0.0014	T
GERP RS		4.3
Varity_R		0.056
gMVP		0.089
Mutation Taster		=100/0	polymorphism (auto)

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: rs3795634; hg19: chr1-200635550; COSMIC: COSV58750950; COSMIC: COSV58750950;