1-200644517-T-C

Position:

chr1-200644517-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_ModerateBP6_ModerateBS1

The NM_001031725.6(DDX59):c.1597A>G(p.Ile533Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,561,976 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

DDX59
NM_001031725.6 missense, splice_region

Scores

Splicing: ADA: 0.00005865

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.398

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12597764).

BP6

Variant 1-200644517-T-C is Benign according to our data. Variant chr1-200644517-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3081179.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000177 (27/152198) while in subpopulation AMR AF= 0.00164 (25/15282). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX59	NM_001031725.6 linkuse as main transcript	c.1597A>G	p.Ile533Val	missense_variant, splice_region_variant	8/8	ENST00000331314.11	NP_001026895.2	Q5T1V6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX59	ENST00000331314.11 linkuse as main transcript	c.1597A>G	p.Ile533Val	missense_variant, splice_region_variant	8/8	1	NM_001031725.6	ENSP00000330460.6		Q5T1V6-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00000952

AC:

AN:

210004

Hom.:

AF XY:

0.0000175

AC XY:

AN XY:

114096

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000859

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000163

AC:

AN:

1409778

Hom.:

Cov.:

AF XY:

0.0000200

AC XY:

AN XY:

698642

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000292

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:

0.000224

GnomAD4 genome

AF:

0.000177

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000487

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.39

CADD

Benign

4.3

DANN

Benign

0.80

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.19

N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T

Sift4G

Benign

0.67

T;.

Polyphen

0.0

B;.

Vest4

0.14

MutPred

0.68

Gain of disorder (P = 0.1064);.;

MVP

0.60

MPC

0.14

ClinPred

0.029

GERP RS

-0.63

Varity_R

0.012

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000059

dbscSNV1_RF

Benign

0.0040

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