rs151210946

chr12-31102263-C-Gchr12-31102263-C-T

Variant summary

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

The NM_030653.4(DDX11):c.2223C>G(p.Ser741Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,970 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: DDX11 NM_030653.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.55

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033525825).
• BP6: Variant 12-31102263-C-G is Benign according to our data. Variant chr12-31102263-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 235586.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 = 0.0128 (1943/152316) while in subpopulation AFR AF= 0.0438 (1822/41558). AF 95% confidence interval is 0.0422. There are 37 homozygotes in gnomad4. There are 960 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX11	NM_030653.4	c.2223C>G	p.Ser741Arg	missense_variant	22/27	ENST00000542838.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX11	ENST00000542838.6	c.2223C>G	p.Ser741Arg	missense_variant	22/27	1	NM_030653.4	P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1942 AN: 152198 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

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: 0.000118

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00306 AC: 769 AN: 251462 Hom.: 17 AF XY: 0.00230 AC XY: 312 AN XY: 135914

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.00214

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: 0.0000791

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00122 AC: 1777 AN: 1461654 Hom.: 34 Cov.: 32 AF XY: 0.00107 AC XY: 780 AN XY: 727148

Gnomad4 AFR exome AF: 0.0440

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.0128 AC: 1943 AN: 152316 Hom.: 37 Cov.: 33 AF XY: 0.0129 AC XY: 960 AN XY: 74478

Gnomad4 AFR AF: 0.0438

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.000651 Hom.: 1

Bravo AF: 0.0142

ESP6500AA AF: 0.0411 AC: 181

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00375 AC: 455

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	5.1
Dann	Benign	0.12
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.84	T;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.57	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.83	T;T;T;T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.24
MutPred		0.36		Gain of MoRF binding (P = 0.0173);.;Gain of MoRF binding (P = 0.0173);.;
MVP		0.73
ClinPred		0.0025	T
GERP RS		-0.32
Varity_R		0.049
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs151210946; hg19: chr12-31255197;