12-31096291-T-C

Variant names:

• chr12-31096291-T-C
• rs9788047
• NM_030653.4:c.1483-50T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_030653.4(DDX11):​c.1483-50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,127,988 control chromosomes in the GnomAD database, including 99,063 homozygotes. 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: 𝑓 0.53 (21853 hom., cov: 25)
  • Exomes 𝑓: 0.28 (77210 hom.)
• Consequence: DDX11 NM_030653.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BS2: High Homozygotes in GnomAd4 at 21853 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX11	NM_030653.4	MANE Select	c.1483-50T>C		intron	N/A	NP_085911.2
	DDX11	NM_001257144.2		c.1483-50T>C		intron	N/A	NP_001244073.1
	DDX11	NM_001413695.1		c.1483-50T>C		intron	N/A	NP_001400624.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX11	ENST00000542838.6	TSL:1 MANE Select	c.1483-50T>C		intron	N/A	ENSP00000443426.1
	DDX11	ENST00000545668.5	TSL:1	c.1483-50T>C		intron	N/A	ENSP00000440402.1
	DDX11	ENST00000228264.10	TSL:1	c.1405-50T>C		intron	N/A	ENSP00000228264.6

Frequencies

GnomAD3 genomes AF: 0.529 AC: 77874 AN: 147120 Hom.: 21797 Cov.: 25

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.505

GnomAD2 exomes AF: 0.336 AC: 58292 AN: 173274 AF XY: 0.320

Gnomad AFR exome AF: 0.467

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.722

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.277 AC: 271899 AN: 980746 Hom.: 77210 Cov.: 31 AF XY: 0.285 AC XY: 141874 AN XY: 496952

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.524 AC: 10584 AN: 20194

American (AMR) AF: 0.564 AC: 18798 AN: 33322

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 6409 AN: 21768

East Asian (EAS) AF: 0.814 AC: 27128 AN: 33324

South Asian (SAS) AF: 0.459 AC: 30345 AN: 66176

European-Finnish (FIN) AF: 0.353 AC: 15725 AN: 44494

Middle Eastern (MID) AF: 0.281 AC: 1107 AN: 3934

European-Non Finnish (NFE) AF: 0.206 AC: 147220 AN: 714232

Other (OTH) AF: 0.337 AC: 14583 AN: 43302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.530 AC: 77988 AN: 147242 Hom.: 21853 Cov.: 25 AF XY: 0.531 AC XY: 38068 AN XY: 71716

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.670 AC: 26572 AN: 39650

American (AMR) AF: 0.590 AC: 8749 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1304 AN: 3414

East Asian (EAS) AF: 0.810 AC: 3916 AN: 4836

South Asian (SAS) AF: 0.551 AC: 2469 AN: 4480

European-Finnish (FIN) AF: 0.406 AC: 4161 AN: 10252

Middle Eastern (MID) AF: 0.428 AC: 124 AN: 290

European-Non Finnish (NFE) AF: 0.440 AC: 29277 AN: 66600

Other (OTH) AF: 0.505 AC: 1017 AN: 2014

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.444 Hom.: 2964

Bravo AF: 0.560

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.8
DANN	Benign	0.61
PhyloP100		-0.018
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.070		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: rs9788047; hg19: chr12-31249225; COSMIC: COSV107194302; COSMIC: COSV107194302;