chr12-31083901-A-G

Variant names:

• chr12-31083901-A-G
• rs373242028
• NM_030653.4:c.233A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_030653.4(DDX11):​c.233A>G​(p.Glu78Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,613,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: DDX11 NM_030653.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.789

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05494997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX11	NM_030653.4	c.233A>G	p.Glu78Gly	missense_variant	Exon 3 of 27	ENST00000542838.6	NP_085911.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX11	ENST00000542838.6	c.233A>G	p.Glu78Gly	missense_variant	Exon 3 of 27	1	NM_030653.4	ENSP00000443426.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000132 AC: 33 AN: 249770 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135322

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.0000289

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: 0.000257

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000376 AC: 549 AN: 1461504 Hom.: 0 Cov.: 32 AF XY: 0.000356 AC XY: 259 AN XY: 727050

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

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: 0.000438

Gnomad4 OTH exome AF: 0.000978

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000513 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.0000907 AC: 11

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.233A>G (p.E78G) alteration is located in exon 3 (coding exon 2) of the DDX11 gene. This alteration results from a A to G substitution at nucleotide position 233, causing the glutamic acid (E) at amino acid position 78 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.030	.;.;T;.;T;.;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.055	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N;N;D;N;N;N;N;.
REVEL	Benign	0.0080
Sift	Benign	0.088	T;T;D;T;T;D;T;.
Sift4G	Benign	0.17	T;T;T;T;T;D;T;T
Polyphen		0.0020	B;.;.;.;B;B;.;.
Vest4		0.16
MVP		0.45
ClinPred		0.019	T
GERP RS		2.1
Varity_R		0.11
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373242028; hg19: chr12-31236835;