12-31083922-A-G

Position:

chr12-31083922-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030653.4(DDX11):c.254A>G(p.His85Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00738 in 1,613,924 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 45 hom. )

Consequence

DDX11
NM_030653.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.967

Variant links:

Genes affected

DDX11 (HGNC:2736): (DEAD/H-box helicase 11) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is an enzyme that possesses both ATPase and DNA helicase activities. This gene is a homolog of the yeast CHL1 gene, and may function to maintain chromosome transmission fidelity and genome stability. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

DDX11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004405141).

BP6

Variant 12-31083922-A-G is Benign according to our data. Variant chr12-31083922-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 774326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-31083922-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00757 (11067/1461638) while in subpopulation NFE AF= 0.00893 (9931/1111828). AF 95% confidence interval is 0.00879. There are 45 homozygotes in gnomad4_exome. There are 5363 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX11	NM_030653.4 link	c.254A>G	p.His85Arg	missense_variant	3/27	ENST00000542838.6	NP_085911.2	Q2NKM7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX11	ENST00000542838.6 link	c.254A>G	p.His85Arg	missense_variant	3/27	1	NM_030653.4	ENSP00000443426.1		Q96FC9-2

Frequencies

GnomAD3 genomes

AF:

0.00555

AC:

845

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00885

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00546

AC:

1370

AN:

251010

Hom.:

AF XY:

0.00517

AC XY:

702

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00425

Gnomad ASJ exome

AF:

0.00566

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00651

Gnomad NFE exome

AF:

0.00828

Gnomad OTH exome

AF:

0.00849

GnomAD4 exome

AF:

0.00757

AC:

11067

AN:

1461638

Hom.:

Cov.:

AF XY:

0.00738

AC XY:

5363

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00432

Gnomad4 ASJ exome

AF:

0.00605

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00698

Gnomad4 NFE exome

AF:

0.00893

Gnomad4 OTH exome

AF:

0.00553

GnomAD4 genome

AF:

0.00554

AC:

844

AN:

152286

Hom.:

Cov.:

AF XY:

0.00535

AC XY:

398

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.00686

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00415

Gnomad4 NFE

AF:

0.00885

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00702

Hom.:

Bravo

AF:

0.00530

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00872

AC:

ExAC

AF:

0.00542

AC:

658

EpiCase

AF:

0.00720

EpiControl

AF:

0.00682

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DDX11: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

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

0.056

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.0090

DANN

Benign

0.18

DEOGEN2

Benign

0.0027

.;.;T;.;T;.;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.42

T;T;T;T;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0044

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.29

N;N;N;N;N;N;N;.

REVEL

Benign

0.12

Sift

Benign

0.53

T;T;T;T;T;T;T;.

Sift4G

Benign

0.54

T;T;T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;B;B;.;.

Vest4

0.086

MVP

0.56

ClinPred

0.0018

GERP RS

-8.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.085

gMVP

0.12

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