rs751610886

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_130810.4(DNAAF4):c.523delA(p.Ile175PhefsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,546,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

DNAAF4
NM_130810.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.645

Publications

8 publications found

Variant links:

Genes affected

DNAAF4 (HGNC:21493): (dynein axonemal assembly factor 4) This gene encodes a tetratricopeptide repeat domain-containing protein. The encoded protein interacts with estrogen receptors and the heat shock proteins, Hsp70 and Hsp90. An homologous protein in rat has been shown to function in neuronal migration in the developing neocortex. A chromosomal translocation involving this gene is associated with a susceptibility to developmental dyslexia. Mutations in this gene are associated with deficits in reading and spelling. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream cell cycle progression 1 (CCPG1) gene. [provided by RefSeq, Mar 2011]

DNAAF4 links:

DNAAF4-CCPG1 (HGNC:43019): (DNAAF4-CCPG1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring dyslexia susceptibility 1 candidate 1 (DYX1C1) and cell cycle progression 1 (CCPG1) genes on chromosome 15. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

DNAAF4-CCPG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 15-55467043-AT-A is Pathogenic according to our data. Variant chr15-55467043-AT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 505757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4 link	c.523delA	p.Ile175PhefsTer21	frameshift_variant	Exon 5 of 10	ENST00000321149.7	NP_570722.2	Q8WXU2-1
DNAAF4	NM_001033560.2 link	c.523delA	p.Ile175PhefsTer21	frameshift_variant	Exon 5 of 9		NP_001028732.1	Q8WXU2-2A0A0S2Z5Z4
DNAAF4	NM_001033559.3 link	c.523delA	p.Ile175PhefsTer21	frameshift_variant	Exon 5 of 9		NP_001028731.1	Q8WXU2-3
DNAAF4-CCPG1	NR_037923.1 link	n.778delA		non_coding_transcript_exon_variant	Exon 4 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7 link	c.523delA	p.Ile175PhefsTer21	frameshift_variant	Exon 5 of 10	1	NM_130810.4	ENSP00000323275.3		Q8WXU2-1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000735

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00135

AC:

201

AN:

148830

AF XY:

0.00143

show subpopulations

Gnomad AFR exome

AF:

0.000653

Gnomad AMR exome

AF:

0.00232

Gnomad ASJ exome

AF:

0.000903

Gnomad EAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.000360

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.000166

AC:

232

AN:

1395982

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

127

AN XY:

690550

show subpopulations

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

African (AFR)

AF:

0.000197

AC:

AN:

30480

American (AMR)

AF:

0.00154

AC:

AN:

35094

Ashkenazi Jewish (ASJ)

AF:

0.000321

AC:

AN:

24960

East Asian (EAS)

AF:

0.000167

AC:

AN:

35916

South Asian (SAS)

AF:

0.000533

AC:

AN:

76912

European-Finnish (FIN)

AF:

0.000120

AC:

AN:

50066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.0000917

AC:

AN:

1079380

Other (OTH)

AF:

0.000209

AC:

AN:

57552

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.243

Heterozygous variant carriers

113

150

188

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:

0.0000200

AC:

AN:

150032

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73190

show subpopulations

African (AFR)

AF:

0.0000735

AC:

AN:

40826

American (AMR)

AF:

0.00

AC:

AN:

15028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67420

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00300

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 25

Pathogenic:1

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change deletes 1 nucleotide from exon 5 of the DYX1C1 mRNA (c.523delA), causing a frameshift at codon 175. This creates a premature translational stop signal (p.Ile175Phefs*21) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in DYX1C1 are known to be pathogenic (PMID: 23872636). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -

Primary ciliary dyskinesia

Pathogenic:1

May 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ile175PhefsX21 (NM_130810.3 c.523delA) variant in DNAAF4 has not been prev iously reported in individuals with primary ciliary dyskinesia. This variant has been identified in 0.26% (50/19436) of Latino chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778891601). Alt hough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is pre dicted to cause a frameshift, which alters the protein?s amino acid sequence beg inning at position 175 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the DNAAF4 gene has been associated with primary ciliary dyskinesia. In summary, although additional studies are required to fully establish a null effect on the protein, the p.Ile175PhefsX21 variant i n DNAAF4 gene is likely pathogenic for primary ciliary dyskinesia in an autosoma l recessive manner based on a predicted null effect. -

not provided

Pathogenic:1

Mar 13, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dyslexia, susceptibility to, 1;C3809641:Primary ciliary dyskinesia 25

Pathogenic:1

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.65

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over