4-122947489-G-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_145207.3(AFG2A):c.1714+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_145207.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPATA5 | ENST00000274008.5 | c.1714+1G>C | splice_donor_variant, intron_variant | Intron 9 of 15 | 1 | NM_145207.3 | ENSP00000274008.3 | |||
SPATA5 | ENST00000422835.2 | n.1756+1G>C | splice_donor_variant, intron_variant | Intron 9 of 14 | 1 | |||||
SPATA5 | ENST00000675612.1 | c.1711+1G>C | splice_donor_variant, intron_variant | Intron 9 of 16 | ENSP00000502453.1 | |||||
SPATA5 | ENST00000674886.1 | n.1776+1G>C | splice_donor_variant, intron_variant | Intron 9 of 10 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with epilepsy, hearing loss, and intellectual disability syndrome (PMID: 26299366, 28293831). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 9 of the SPATA5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SPATA5 are known to be pathogenic (PMID: 26299366). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.