11-118754809-T-C

Position:

• chr11-118754809-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_004397.6(DDX6):​c.1355A>G​(p.Gln452Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DDX6 NM_004397.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 5 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDX6	NM_004397.6	c.1355A>G	p.Gln452Arg	missense_variant	13/14	ENST00000534980.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDX6	ENST00000534980.7	c.1355A>G	p.Gln452Arg	missense_variant	13/14	1	NM_004397.6	P1
DDX6	ENST00000526070.2	c.1355A>G	p.Gln452Arg	missense_variant	13/13	1		P1
DDX6	ENST00000620157.4	c.1355A>G	p.Gln452Arg	missense_variant	13/14	1		P1
DDX6	ENST00000529162.1	n.958A>G		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2024

The c.1355A>G (p.Q452R) alteration is located in exon 13 (coding exon 12) of the DDX6 gene. This alteration results from an A to G substitution at nucleotide position 1355, causing the glutamine (Q) at amino acid position 452 to be replaced by an arginine (R). 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). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;.
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.085	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.3	.;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.025	.;D;D
Sift4G	Benign	0.29	T;T;T
Polyphen		0.39	B;B;B
Vest4		0.72
MutPred		0.34		Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.85
ClinPred		0.76	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-118625518;