Variant chr1-200644448-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001031725.6(DDX59):c.1666C>G(p.Leu556Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,938 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 1 hom. )

Consequence

DDX59
NM_001031725.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.82

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX59	NM_001031725.6 linkuse as main transcript	c.1666C>G	p.Leu556Val	missense_variant	8/8	ENST00000331314.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX59	ENST00000331314.11 linkuse as main transcript	c.1666C>G	p.Leu556Val	missense_variant	8/8	1	NM_001031725.6	P1	Q5T1V6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459938

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 29, 2023

ClinVar contains an entry for this variant (Variation ID: 1994347). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DDX59 protein function. This variant has not been reported in the literature in individuals affected with DDX59-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 556 of the DDX59 protein (p.Leu556Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.17

Sift

Uncertain

0.029

D;D

Sift4G

Benign

0.072

T;.

Polyphen

0.97

D;.

Vest4

0.50

MutPred

0.44

Loss of catalytic residue at L556 (P = 0.003);.;

MVP

0.94

MPC

0.46

ClinPred

0.95

GERP RS

5.5

Varity_R

0.27

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over