chr1-200648497-C-T

Variant names:

• chr1-200648497-C-T
• rs142176836
• NM_001031725.6:c.1538G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001031725.6(DDX59):​c.1538G>A​(p.Ser513Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,614,166 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (16 hom.)
• Consequence: DDX59 NM_001031725.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.31
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063795447).
• BP6: Variant 1-200648497-C-T is Benign according to our data. Variant chr1-200648497-C-T is described in ClinVar as Benign. ClinVar VariationId is 728607.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00219 (333/152324) while in subpopulation EAS AF = 0.00347 (18/5190). AF 95% confidence interval is 0.00224. There are 7 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.1538G>A	p.Ser513Asn	missense	Exon 7 of 8	NP_001026895.2	Q5T1V6-1
	DDX59	NM_001349799.3		c.1538G>A	p.Ser513Asn	missense	Exon 7 of 8	NP_001336728.1	Q5T1V6-1
	DDX59	NM_001349800.3		c.1538G>A	p.Ser513Asn	missense	Exon 7 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.1538G>A	p.Ser513Asn	missense	Exon 7 of 8	ENSP00000330460.6	Q5T1V6-1
	DDX59	ENST00000936161.1		c.1538G>A	p.Ser513Asn	missense	Exon 6 of 7	ENSP00000606220.1
	DDX59	ENST00000936162.1		c.1538G>A	p.Ser513Asn	missense	Exon 7 of 8	ENSP00000606221.1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152206 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00264 AC: 663 AN: 251426 AF XY: 0.00250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00185

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00121 AC: 1772 AN: 1461842 Hom.: 16 Cov.: 31 AF XY: 0.00120 AC XY: 873 AN XY: 727222

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26136

East Asian (EAS) AF: 0.00436 AC: 173 AN: 39696

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86254

European-Finnish (FIN) AF: 0.0191 AC: 1020 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.000334 AC: 371 AN: 1111990

Other (OTH) AF: 0.00157 AC: 95 AN: 60394

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152324 Hom.: 7 Cov.: 31 AF XY: 0.00324 AC XY: 241 AN XY: 74488

African (AFR) AF: 0.0000481 AC: 2 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0253 AC: 268 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000957 Hom.: 1

Bravo AF: 0.000382

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	DDX59-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.35
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.3	N
PhyloP100		2.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.093
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.68
MPC		0.16
ClinPred		0.017	T
GERP RS		2.2
Varity_R		0.032
gMVP		0.22
Mutation Taster		=100/0	polymorphism

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: rs142176836; hg19: chr1-200617625; COSMIC: COSV58750858; COSMIC: COSV58750858;