11-118755506-TAAAA-TAAAAA

Variant names:

• chr11-118755506-T-TA
• rs551201488
• NM_004397.6:c.1175-4dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_004397.6(DDX6):​c.1175-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 1,145,874 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1 hom.)
• Consequence: DDX6 NM_004397.6 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0610
• 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 -5 ACMG points.

• BP6: Variant 11-118755506-T-TA is Benign according to our data. Variant chr11-118755506-T-TA is described in ClinVar as Likely_benign. ClinVar VariationId is 3059409.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 137 AD gene.

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.1175-4dupT		splice_region intron	N/A	NP_004388.2	P26196
	DDX6	NM_001257191.3		c.1175-4dupT		splice_region intron	N/A	NP_001244120.1	P26196
	DDX6	NM_001425145.1		c.1175-4dupT		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.1175-4_1175-3insT		splice_region intron	N/A	ENSP00000442266.1	P26196
	DDX6	ENST00000526070.2	TSL:1	c.1175-4_1175-3insT		splice_region intron	N/A	ENSP00000433704.1	P26196
	DDX6	ENST00000620157.4	TSL:1	c.1175-4_1175-3insT		splice_region intron	N/A	ENSP00000478754.1	P26196

Frequencies

GnomAD3 genomes AF: 0.000939 AC: 138 AN: 146898 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000895

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00156

Gnomad SAS AF: 0.00128

Gnomad FIN AF: 0.000759

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000995

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0188 AC: 2381 AN: 126892 AF XY: 0.0186

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.0199

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0338 AC: 33776 AN: 998890 Hom.: 1 Cov.: 18 AF XY: 0.0333 AC XY: 16519 AN XY: 496488

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

African (AFR) AF: 0.0308 AC: 683 AN: 22208

American (AMR) AF: 0.0254 AC: 726 AN: 28638

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 506 AN: 16128

East Asian (EAS) AF: 0.0250 AC: 619 AN: 24724

South Asian (SAS) AF: 0.0308 AC: 1700 AN: 55164

European-Finnish (FIN) AF: 0.0259 AC: 908 AN: 35032

Middle Eastern (MID) AF: 0.0258 AC: 109 AN: 4228

European-Non Finnish (NFE) AF: 0.0351 AC: 27108 AN: 773170

Other (OTH) AF: 0.0358 AC: 1417 AN: 39598

⚠️ 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 AF: 0.000932 AC: 137 AN: 146984 Hom.: 0 Cov.: 32 AF XY: 0.000952 AC XY: 68 AN XY: 71446

African (AFR) AF: 0.000893 AC: 36 AN: 40310

American (AMR) AF: 0.00102 AC: 15 AN: 14736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00137 AC: 7 AN: 5110

South Asian (SAS) AF: 0.00128 AC: 6 AN: 4672

European-Finnish (FIN) AF: 0.000759 AC: 7 AN: 9222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000995 AC: 66 AN: 66318

Other (OTH) AF: 0.00 AC: 0 AN: 2030

Alfa AF: 0.0316 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	DDX6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.061
Mutation Taster		=100/0	polymorphism

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

dbSNP: rs551201488; hg19: chr11-118626215; COSMIC: COSV50591114;