11-118756278-G-A

Variant names:

• chr11-118756278-G-A
• rs782274778
• NM_004397.6:c.1156C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_004397.6(DDX6):​c.1156C>T​(p.Arg386Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,220 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DDX6 NM_004397.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.75

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a mutagenesis_site Abolished ability to regulate RNA metabolism. (size 0) in uniprot entity DDX6_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 11-118756278-G-A is Pathogenic according to our data. Variant chr11-118756278-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2441657.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDX6	NM_004397.6	c.1156C>T	p.Arg386Cys	missense_variant	Exon 11 of 14	ENST00000534980.7	NP_004388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDX6	ENST00000534980.7	c.1156C>T	p.Arg386Cys	missense_variant	Exon 11 of 14	1	NM_004397.6	ENSP00000442266.1
DDX6	ENST00000526070.2	c.1156C>T	p.Arg386Cys	missense_variant	Exon 11 of 13	1		ENSP00000433704.1
DDX6	ENST00000620157.4	c.1156C>T	p.Arg386Cys	missense_variant	Exon 11 of 14	1		ENSP00000478754.1
DDX6	ENST00000529162.1	n.759C>T		non_coding_transcript_exon_variant	Exon 3 of 6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461220 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726928

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: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Aug 09, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1156C>T (p.R386C) alteration is located in exon 11 (coding exon 10) of the DDX6 gene. This alteration results from a C to T substitution at nucleotide position 1156, causing the arginine (R) at amino acid position 386 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Intellectual developmental disorder with impaired language and dysmorphic facies Pathogenic:1

Mar 18, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DDX6: PM2:Supporting, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;.
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-8.0	.;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.77
MutPred		0.72		Loss of MoRF binding (P = 0.0626);Loss of MoRF binding (P = 0.0626);Loss of MoRF binding (P = 0.0626);
MVP		0.93
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.91

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: rs782274778; hg19: chr11-118626987; COSMIC: COSV99870550;