NM_030653.4:c.2223C>G

Variant names:

• chr12-31102263-C-G
• rs151210946
• NM_030653.4:c.2223C>G

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S741N) has been classified as Uncertain significance.

• 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:3
• Conservation: PhyloP100: 1.55
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Warsaw breakage syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030653.4. 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
	DDX11	NM_030653.4	MANE Select	c.2223C>G	p.Ser741Arg	missense	Exon 22 of 27	NP_085911.2	Q96FC9-2
	DDX11	NM_001257144.2		c.2223C>G	p.Ser741Arg	missense	Exon 22 of 27	NP_001244073.1	Q96FC9-1
	DDX11	NM_001413695.1		c.2223C>G	p.Ser741Arg	missense	Exon 24 of 29	NP_001400624.1	Q96FC9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX11	ENST00000542838.6	TSL:1 MANE Select	c.2223C>G	p.Ser741Arg	missense	Exon 22 of 27	ENSP00000443426.1	Q96FC9-2
	DDX11	ENST00000545668.5	TSL:1	c.2223C>G	p.Ser741Arg	missense	Exon 22 of 27	ENSP00000440402.1	Q96FC9-1
	DDX11	ENST00000228264.10	TSL:1	c.2145C>G	p.Ser715Arg	missense	Exon 22 of 27	ENSP00000228264.6	Q96FC9-3

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

GnomAD2 exomes AF: 0.00306 AC: 769 AN: 251462 AF XY: 0.00230

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 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

African (AFR) AF: 0.0440 AC: 1472 AN: 33472

American (AMR) AF: 0.00219 AC: 98 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111814

Other (OTH) AF: 0.00210 AC: 127 AN: 60382

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

African (AFR) AF: 0.0438 AC: 1822 AN: 41558

American (AMR) AF: 0.00660 AC: 101 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.86	T
PhyloP100		1.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.18
Sift	Benign	0.83	T
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.36		Gain of MoRF binding (P = 0.0173)
MVP		0.73
ClinPred		0.0025	T
GERP RS		-0.32
PromoterAI		0.034	Neutral
Varity_R		0.049
gMVP		0.21
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs151210946; hg19: chr12-31255197;