NM_004397.6:c.1231T>C

Variant names:

• chr11-118755447-A-G
• NM_004397.6:c.1231T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_004397.6(DDX6):​c.1231T>C​(p.Phe411Leu) 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. 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: 9.19
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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 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, 0.78

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.1231T>C	p.Phe411Leu	missense	Exon 12 of 14	NP_004388.2	P26196
	DDX6	NM_001257191.3		c.1231T>C	p.Phe411Leu	missense	Exon 12 of 14	NP_001244120.1	P26196
	DDX6	NM_001425145.1		c.1231T>C	p.Phe411Leu	missense	Exon 12 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.1231T>C	p.Phe411Leu	missense	Exon 12 of 14	ENSP00000442266.1	P26196
	DDX6	ENST00000526070.2	TSL:1	c.1231T>C	p.Phe411Leu	missense	Exon 12 of 13	ENSP00000433704.1	P26196
	DDX6	ENST00000620157.4	TSL:1	c.1231T>C	p.Phe411Leu	missense	Exon 12 of 14	ENSP00000478754.1	P26196

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual developmental disorder with impaired language and dysmorphic facies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.48	N
PhyloP100		9.2
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.62
Sift	Benign	0.42	T
Sift4G	Benign	0.91	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.48		Loss of helix (P = 0.0558)
MVP		0.86
ClinPred		0.97	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.95
Mutation Taster		=46/54	disease causing

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

Other links and lift over

hg19: chr11-118626156;