12-31084584-C-T

Position:

• chr12-31084584-C-T

Variant summary

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

The NM_030653.4(DDX11):​c.395C>T​(p.Ala132Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00084 in 1,593,454 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (1 hom.)
• Consequence: DDX11 NM_030653.4 missense, splice_region
• Scores: Splicing: ADA: 0.000006794
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.42

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 (HGNC:):

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=0.012879282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX11	NM_030653.4	c.395C>T	p.Ala132Val	missense_variant, splice_region_variant	4/27	ENST00000542838.6	NP_085911.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX11	ENST00000542838.6	c.395C>T	p.Ala132Val	missense_variant, splice_region_variant	4/27	1	NM_030653.4	ENSP00000443426.1

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000445 AC: 98 AN: 220240 Hom.: 0 AF XY: 0.000460 AC XY: 55 AN XY: 119642

Gnomad AFR exome AF: 0.000314

Gnomad AMR exome AF: 0.000498

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000781

Gnomad OTH exome AF: 0.000363

GnomAD4 exome AF: 0.000857 AC: 1235 AN: 1441176 Hom.: 1 Cov.: 31 AF XY: 0.000807 AC XY: 577 AN XY: 715382

Gnomad4 AFR exome AF: 0.000515

Gnomad4 AMR exome AF: 0.000376

Gnomad4 ASJ exome AF: 0.000117

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.0000765

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.000873

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74450

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000983 Hom.: 0

Bravo AF: 0.000706

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000437 AC: 53

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.072	.;.;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.36	T;T;T;T;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.98	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.25	T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T
Polyphen		0.0010	B;.;.;B;B;.
Vest4		0.24
MVP		0.16
ClinPred		0.024	T
GERP RS		0.18
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.039
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000068
dbscSNV1_RF	Benign	0.0
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: rs150544555; hg19: chr12-31237518; COSMIC: COSV99300009; COSMIC: COSV99300009;