rs748763190
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_130810.4(DNAAF4):c.893+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.0000634 in 1,609,272 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000065 ( 0 hom. )
Consequence
DNAAF4
NM_130810.4 splice_donor_5th_base, intron
NM_130810.4 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9923
2
Clinical Significance
Conservation
PhyloP100: 6.42
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF4 | NM_130810.4 | c.893+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000321149.7 | |||
DNAAF4-CCPG1 | NR_037923.1 | n.1148+5G>A | splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant | ||||
DNAAF4 | NM_001033559.3 | c.893+5G>A | splice_donor_5th_base_variant, intron_variant | ||||
DNAAF4 | NM_001033560.2 | c.893+5G>A | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF4 | ENST00000321149.7 | c.893+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_130810.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250972Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135684
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GnomAD4 exome AF: 0.0000652 AC: 95AN: 1457106Hom.: 0 Cov.: 29 AF XY: 0.0000676 AC XY: 49AN XY: 725228
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74332
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2021 | This sequence change falls in intron 7 of the DNAAF4 gene. It does not directly change the encoded amino acid sequence of the DNAAF4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs748763190, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNAAF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 241834). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at