chr4-122927721-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_145207.3(AFG2A):c.251G>A(p.Arg84Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,612,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_145207.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPATA5 | ENST00000274008.5 | c.251G>A | p.Arg84Gln | missense_variant | Exon 2 of 16 | 1 | NM_145207.3 | ENSP00000274008.3 | ||
SPATA5 | ENST00000422835.2 | n.293G>A | non_coding_transcript_exon_variant | Exon 2 of 15 | 1 | |||||
SPATA5 | ENST00000675612.1 | c.248G>A | p.Arg83Gln | missense_variant | Exon 2 of 17 | ENSP00000502453.1 | ||||
SPATA5 | ENST00000674886.1 | n.313G>A | non_coding_transcript_exon_variant | Exon 2 of 11 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000719 AC: 18AN: 250482Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135360
GnomAD4 exome AF: 0.0000479 AC: 70AN: 1460862Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 36AN XY: 726704
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74304
ClinVar
Submissions by phenotype
Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Pathogenic:2
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 84 of the SPATA5 protein (p.Arg84Gln). This variant is present in population databases (rs745858366, gnomAD 0.01%). This missense change has been observed in individual(s) with epilepsy, hearing loss, and intellectual disability syndrome (PMID: 26299366, 28513609; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203534). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPATA5 protein function. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: AFG2A c.251G>A (p.Arg84Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.7e-05 in 281868 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AFG2A causing Epilepsy, Hearing Loss, And Mental Retardation Syndrome, allowing no conclusion about variant significance. c.251G>A has been reported in the literature in multiple individuals affected with Epilepsy, Hearing Loss, And Mental Retardation Syndrome, or with cerebral palsy (e.g. Tanaka_2015, Truty_2019, Moreno-De-Luca_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26299366, 31440721, 33528536). ClinVar contains an entry for this variant (Variation ID: 203534). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26299366, 29343804, 28513609, 33528536, 31440721) -
Neurodevelopmental disorder Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at