rs138980593

Variant names:

• chr12-31083922-A-G
• rs138980593
• NM_030653.4:c.254A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-31083922-A-G
• chr12-31083922-A-T

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.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. 15/21 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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.967
• Publications: 4 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 774326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 5363 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.254A>G	p.His85Arg	missense	Exon 3 of 27	NP_085911.2	Q96FC9-2
	DDX11	NM_001257144.2		c.254A>G	p.His85Arg	missense	Exon 3 of 27	NP_001244073.1	Q96FC9-1
	DDX11	NM_001413695.1		c.254A>G	p.His85Arg	missense	Exon 5 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.254A>G	p.His85Arg	missense	Exon 3 of 27	ENSP00000443426.1	Q96FC9-2
	DDX11	ENST00000545668.5	TSL:1	c.254A>G	p.His85Arg	missense	Exon 3 of 27	ENSP00000440402.1	Q96FC9-1
	DDX11	ENST00000228264.10	TSL:1	c.176A>G	p.His59Arg	missense	Exon 3 of 27	ENSP00000228264.6	Q96FC9-3

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 845 AN: 152168 Hom.: 6 Cov.: 32

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

GnomAD2 exomes AF: 0.00546 AC: 1370 AN: 251010 AF XY: 0.00517

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 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.: 45 Cov.: 33 AF XY: 0.00738 AC XY: 5363 AN XY: 727136

African (AFR) AF: 0.00105 AC: 35 AN: 33472

American (AMR) AF: 0.00432 AC: 193 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 158 AN: 26130

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

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86250

European-Finnish (FIN) AF: 0.00698 AC: 373 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5746

European-Non Finnish (NFE) AF: 0.00893 AC: 9931 AN: 1111828

Other (OTH) AF: 0.00553 AC: 334 AN: 60378

GnomAD4 genome AF: 0.00554 AC: 844 AN: 152286 Hom.: 6 Cov.: 32 AF XY: 0.00535 AC XY: 398 AN XY: 74460

African (AFR) AF: 0.00159 AC: 66 AN: 41554

American (AMR) AF: 0.00686 AC: 105 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00885 AC: 602 AN: 68030

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00702 Hom.: 1

Bravo AF: 0.00530

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.00542 AC: 658

EpiCase AF: 0.00720

EpiControl AF: 0.00682

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.0090
DANN	Benign	0.18
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.97
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.12
Sift	Benign	0.53	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.086
MVP		0.56
ClinPred		0.0018	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.085
gMVP		0.12
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs138980593; hg19: chr12-31236856;