11-118756262-G-A

Position:

• chr11-118756262-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_004397.6(DDX6):​c.1172C>T​(p.Thr391Ile) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DDX6 NM_004397.6 missense, splice_region
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.72

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]

DDX6 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• 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, 0.942
• PP5: Variant 11-118756262-G-A is Pathogenic according to our data. Variant chr11-118756262-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 694351.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX6	NM_004397.6	c.1172C>T	p.Thr391Ile	missense_variant, splice_region_variant	11/14	ENST00000534980.7	NP_004388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX6	ENST00000534980.7	c.1172C>T	p.Thr391Ile	missense_variant, splice_region_variant	11/14	1	NM_004397.6	ENSP00000442266.1
DDX6	ENST00000526070.2	c.1172C>T	p.Thr391Ile	missense_variant, splice_region_variant	11/13	1		ENSP00000433704.1
DDX6	ENST00000620157.4	c.1172C>T	p.Thr391Ile	missense_variant, splice_region_variant	11/14	1		ENSP00000478754.1
DDX6	ENST00000529162.1	n.775C>T		splice_region_variant, 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:2

Revision: criteria provided, single submitter

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

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2022

De novo variant with confirmed parentage in a patient with developmental disorder (Balak et al., 2019); Published functional studies suggest a damaging effect (Balak et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31422817) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;.;.
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.2	M;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.8	.;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.87
MutPred		0.82		Gain of MoRF binding (P = 0.1903);Gain of MoRF binding (P = 0.1903);Gain of MoRF binding (P = 0.1903);
MVP		0.84
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.65
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: rs1591885290; hg19: chr11-118626971;