Genetic Variant DDX6:c.1175-5_1175-4dupTT (chr11-118755506-T-TAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004397.6(DDX6):c.1175-5_1175-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,238,376 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

DDX6
NM_004397.6 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0610

Publications

0 publications found

Variant links:

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

DDX6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DDX6	NM_004397.6	MANE Select	c.1175-5_1175-4dupTT	splice_region intron	N/A	NP_004388.2	P26196
DDX6	NM_001257191.3		c.1175-5_1175-4dupTT	splice_region intron	N/A	NP_001244120.1	P26196
DDX6	NM_001425145.1		c.1175-5_1175-4dupTT	splice_region intron	N/A	NP_001412074.1	P26196

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DDX6	ENST00000534980.7	TSL:1 MANE Select	c.1175-4_1175-3insTT	splice_region intron	N/A	ENSP00000442266.1	P26196
DDX6	ENST00000526070.2	TSL:1	c.1175-4_1175-3insTT	splice_region intron	N/A	ENSP00000433704.1	P26196
DDX6	ENST00000620157.4	TSL:1	c.1175-4_1175-3insTT	splice_region intron	N/A	ENSP00000478754.1	P26196

Frequencies

GnomAD3 genomes

AF:

0.0000136

AC:

AN:

146978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000134

AC:

AN:

126892

AF XY:

0.0000585

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000103

Gnomad FIN exome

AF:

0.0000933

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000110

AC:

120

AN:

1091398

Hom.:

Cov.:

AF XY:

0.0000934

AC XY:

AN XY:

546112

show subpopulations

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

African (AFR)

AF:

0.0000813

AC:

AN:

24604

American (AMR)

AF:

0.000497

AC:

AN:

32214

Ashkenazi Jewish (ASJ)

AF:

0.000212

AC:

AN:

18870

East Asian (EAS)

AF:

0.0000340

AC:

AN:

29382

South Asian (SAS)

AF:

0.0000317

AC:

AN:

63126

European-Finnish (FIN)

AF:

0.000126

AC:

AN:

39620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4558

European-Non Finnish (NFE)

AF:

0.000105

AC:

AN:

834778

Other (OTH)

AF:

0.0000452

AC:

AN:

44246

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.265

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000136

AC:

AN:

146978

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

71398

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

40216

American (AMR)

AF:

0.000136

AC:

AN:

14730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66352

Other (OTH)

AF:

0.00

AC:

AN:

2020

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.061

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-118755506-TAAAA-TAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over