11-118756316-C-T

Position:

• chr11-118756316-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_004397.6(DDX6):​c.1118G>A​(p.Arg373Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DDX6 NM_004397.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.69

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.

• PM1: In a domain Helicase C-terminal (size 160) in uniprot entity DDX6_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_004397.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DDX6. . Trascript score misZ 4.2715 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, intellectual developmental disorder with impaired language and dysmorphic facies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 11-118756316-C-T is Pathogenic according to our data. Variant chr11-118756316-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 694349.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX6	NM_004397.6	c.1118G>A	p.Arg373Gln	missense_variant	11/14	ENST00000534980.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX6	ENST00000534980.7	c.1118G>A	p.Arg373Gln	missense_variant	11/14	1	NM_004397.6	P1
DDX6	ENST00000526070.2	c.1118G>A	p.Arg373Gln	missense_variant	11/13	1		P1
DDX6	ENST00000620157.4	c.1118G>A	p.Arg373Gln	missense_variant	11/14	1		P1
DDX6	ENST00000529162.1	n.721G>A		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;.
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.2	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.0	.;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.91
MutPred		0.88		Loss of MoRF binding (P = 0.0666);Loss of MoRF binding (P = 0.0666);Loss of MoRF binding (P = 0.0666);
MVP		0.93
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.96

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: rs1591885383; hg19: chr11-118627025; COSMIC: COSV50588745;