rs1591885290

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T391P) has been classified 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with impaired language and dysmorphic facies

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-118756263-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 694352.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: 4.2715 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 VariationId is 694351.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004397.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX6	NM_004397.6	MANE Select	c.1172C>T	p.Thr391Ile	missense splice_region	Exon 11 of 14	NP_004388.2	P26196
	DDX6	NM_001257191.3		c.1172C>T	p.Thr391Ile	missense splice_region	Exon 11 of 14	NP_001244120.1	P26196
	DDX6	NM_001425145.1		c.1172C>T	p.Thr391Ile	missense splice_region	Exon 11 of 14	NP_001412074.1	P26196

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDX6	ENST00000534980.7	TSL:1 MANE Select	c.1172C>T	p.Thr391Ile	missense splice_region	Exon 11 of 14	ENSP00000442266.1	P26196
	DDX6	ENST00000526070.2	TSL:1	c.1172C>T	p.Thr391Ile	missense splice_region	Exon 11 of 13	ENSP00000433704.1	P26196
	DDX6	ENST00000620157.4	TSL:1	c.1172C>T	p.Thr391Ile	missense splice_region	Exon 11 of 14	ENSP00000478754.1	P26196

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder with impaired language and dysmorphic facies (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.82		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1591885290; hg19: chr11-118626971;