12-31083922-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001413703.1(DDX11):​c.-275A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DDX11 NM_001413703.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062450916).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413703.1. 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>T	p.His85Leu	missense	Exon 3 of 27	NP_085911.2	Q96FC9-2
	DDX11	NM_001413703.1		c.-275A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 26	NP_001400632.1
	DDX11	NM_001413704.1		c.-807A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 28	NP_001400633.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX11	ENST00000542838.6	TSL:1 MANE Select	c.254A>T	p.His85Leu	missense	Exon 3 of 27	ENSP00000443426.1	Q96FC9-2
	DDX11	ENST00000545668.5	TSL:1	c.254A>T	p.His85Leu	missense	Exon 3 of 27	ENSP00000440402.1	Q96FC9-1
	DDX11	ENST00000228264.10	TSL:1	c.176A>T	p.His59Leu	missense	Exon 3 of 27	ENSP00000228264.6	Q96FC9-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251010 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461650 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111840

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.020
DANN	Benign	0.42
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.91	T
PhyloP100		-0.97
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.12
Sift	Benign	0.32	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.23
MutPred		0.38		Gain of catalytic residue at H85 (P = 0)
MVP		0.36
ClinPred		0.076	T
GERP RS		-8.0
Varity_R		0.14
gMVP		0.21
Mutation Taster		=99/1	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;