rs1308309432

Variant names:

• chr11-118756329-A-C
• rs1308309432
• NM_004397.6:c.1111-6T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004397.6(DDX6):​c.1111-6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DDX6 NM_004397.6 splice_region, intron
• Scores: Splicing: ADA: 0.02249
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).

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.1111-6T>G		splice_region intron	N/A	NP_004388.2	P26196
	DDX6	NM_001257191.3		c.1111-6T>G		splice_region intron	N/A	NP_001244120.1	P26196
	DDX6	NM_001425145.1		c.1111-6T>G		splice_region intron	N/A	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.1111-6T>G		splice_region intron	N/A	ENSP00000442266.1	P26196
	DDX6	ENST00000526070.2	TSL:1	c.1111-6T>G		splice_region intron	N/A	ENSP00000433704.1	P26196
	DDX6	ENST00000620157.4	TSL:1	c.1111-6T>G		splice_region intron	N/A	ENSP00000478754.1	P26196

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459306 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726044

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109834

Other (OTH) AF: 0.0000166 AC: 1 AN: 60312

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

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
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.022
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.010		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: rs1308309432; hg19: chr11-118627038;