11-118756262-G-A

Variant names:

• chr11-118756262-G-A
• rs1591885290
• NM_004397.6:c.1172C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
DDX6	NM_004397.6	c.1172C>T	p.Thr391Ile	missense_variant, splice_region_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.1172C>T	p.Thr391Ile	missense_variant, splice_region_variant	Exon 11 of 14	1	NM_004397.6	ENSP00000442266.1
DDX6	ENST00000526070.2	c.1172C>T	p.Thr391Ile	missense_variant, splice_region_variant	Exon 11 of 13	1		ENSP00000433704.1
DDX6	ENST00000620157.4	c.1172C>T	p.Thr391Ile	missense_variant, splice_region_variant	Exon 11 of 14	1		ENSP00000478754.1
DDX6	ENST00000529162.1	n.775C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 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

Nov 08, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;