chr11-118755492-G-A

Variant names:

• chr11-118755492-G-A
• rs1555158525
• NM_004397.6:c.1186C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004397.6(DDX6):​c.1186C>T​(p.Arg396*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000209 in 1,434,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DDX6 NM_004397.6 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

Genes affected

DDX6 (HGNC:2747): (DEAD-box helicase 6) This gene encodes a member of the DEAD box protein family. The protein is an RNA helicase found in P-bodies and stress granules, and functions in translation suppression and mRNA degradation. It is required for microRNA-induced gene silencing. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX6	NM_004397.6	c.1186C>T	p.Arg396*	stop_gained	Exon 12 of 14	ENST00000534980.7	NP_004388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX6	ENST00000534980.7	c.1186C>T	p.Arg396*	stop_gained	Exon 12 of 14	1	NM_004397.6	ENSP00000442266.1
DDX6	ENST00000526070.2	c.1186C>T	p.Arg396*	stop_gained	Exon 12 of 13	1		ENSP00000433704.1
DDX6	ENST00000620157.4	c.1186C>T	p.Arg396*	stop_gained	Exon 12 of 14	1		ENSP00000478754.1
DDX6	ENST00000529162.1	n.789C>T		non_coding_transcript_exon_variant	Exon 4 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243462 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1434234 Hom.: 0 Cov.: 26 AF XY: 0.00000280 AC XY: 2 AN XY: 714914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 9.17e-7

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DDX6 c.1186C>T (p.Arg396X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in DDX6 as causative of disease. The variant allele was found at a frequency of 4.1e-06 in 243462 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1186C>T in individuals affected with Intellectual Developmental Disorder With Impaired Language And Dysmorphic Facies and no experimental evidence supporting haploinsufficiency of DDX6 as mechanism of disease have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.87
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555158525; hg19: chr11-118626201;