Genetic Variant DNAAF4:p.Ile175LysfsTer22 (chr15-55467043-A-ATT) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_130810.4(DNAAF4):c.522_523dupAA(p.Ile175LysfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,302 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

DNAAF4
NM_130810.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.645

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4 link	c.522_523dupAA	p.Ile175LysfsTer22	frameshift_variant	Exon 5 of 10	ENST00000321149.7	NP_570722.2	Q8WXU2-1
DNAAF4	NM_001033560.2 link	c.522_523dupAA	p.Ile175LysfsTer22	frameshift_variant	Exon 5 of 9		NP_001028732.1	Q8WXU2-2A0A0S2Z5Z4
DNAAF4	NM_001033559.3 link	c.522_523dupAA	p.Ile175LysfsTer22	frameshift_variant	Exon 5 of 9		NP_001028731.1	Q8WXU2-3
DNAAF4-CCPG1	NR_037923.1 link	n.777_778dupAA		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.522_523dupAA	p.Ile175LysfsTer22	frameshift_variant	Exon 5 of 10	1	NM_130810.4	ENSP00000323275.3		Q8WXU2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399302

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692300

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30562

American (AMR)

AF:

0.00

AC:

AN:

35368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25054

East Asian (EAS)

AF:

0.00

AC:

AN:

36032

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081494

Other (OTH)

AF:

0.00

AC:

AN:

57742

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.65

Mutation Taster

=11/189

disease causing (fs/PTC)

(source)

Splicing

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

Publications

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15-55467043-AT-ATTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over