1-200649118-T-C

Position:

• chr1-200649118-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001031725.6(DDX59):​c.1423A>G​(p.Ile475Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000911 in 1,583,544 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 30)
  • Exomes 𝑓: 0.00057 (1 hom.)
• Consequence: DDX59 NM_001031725.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.57

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015464991).
• BP6: Variant 1-200649118-T-C is Benign according to our data. Variant chr1-200649118-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 730282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0041 (624/152308) while in subpopulation AFR AF= 0.014 (580/41566). AF 95% confidence interval is 0.013. There are 3 homozygotes in gnomad4. There are 310 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX59	NM_001031725.6	c.1423A>G	p.Ile475Val	missense_variant	6/8	ENST00000331314.11	NP_001026895.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX59	ENST00000331314.11	c.1423A>G	p.Ile475Val	missense_variant	6/8	1	NM_001031725.6	ENSP00000330460.6

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 624 AN: 152190 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00117 AC: 264 AN: 224822 Hom.: 0 AF XY: 0.000799 AC XY: 98 AN XY: 122644

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000380

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000372

GnomAD4 exome AF: 0.000572 AC: 819 AN: 1431236 Hom.: 1 Cov.: 33 AF XY: 0.000524 AC XY: 373 AN XY: 712162

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.000721

Gnomad4 ASJ exome AF: 0.0000401

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000745

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000226

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152308 Hom.: 3 Cov.: 30 AF XY: 0.00416 AC XY: 310 AN XY: 74478

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000910 Hom.: 0

Bravo AF: 0.00462

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DDX59: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T;T;T;T
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.63	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.13	T;D;T;T
Sift4G	Benign	0.081	T;T;T;.
Polyphen		0.011	.;.;B;.
Vest4		0.090
MVP		0.64
MPC		0.15
ClinPred		0.0073	T
GERP RS		2.5
Varity_R		0.030
gMVP		0.22

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: rs79204709; hg19: chr1-200618246;