rs552219028
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5
The NM_145207.3(SPATA5):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,614,182 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
SPATA5
NM_145207.3 start_lost
NM_145207.3 start_lost
Scores
8
2
6
Clinical Significance
Conservation
PhyloP100: 3.39
Genes affected
AFG2A (HGNC:18119): (AFG2 AAA ATPase homolog A) This gene encodes a member of the ATPase associated with diverse activities family, whose members are defined by a highly conserved ATPase domain. Members of this family participate in diverse cellular processes that include membrane fusion, DNA replication, microtubule severing, and protein degradation. The protein encoded by this gene has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Allelic variants in this gene have been associated with epilepsy, hearing loss, and cognitive disability syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_145207.3 (SPATA5) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 475728
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-122923143-A-C is Pathogenic according to our data. Variant chr4-122923143-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203533.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=2}. Variant chr4-122923143-A-C is described in Lovd as [Likely_pathogenic]. Variant chr4-122923143-A-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPATA5 | NM_145207.3 | c.1A>C | p.Met1? | start_lost | 1/16 | ENST00000274008.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AFG2A | ENST00000274008.5 | c.1A>C | p.Met1? | start_lost | 1/16 | 1 | NM_145207.3 | P1 | |
AFG2A | ENST00000422835.2 | n.43A>C | non_coding_transcript_exon_variant | 1/15 | 1 | ||||
AFG2A | ENST00000675612.1 | c.1A>C | p.Met1? | start_lost | 1/17 | ||||
AFG2A | ENST00000674886.1 | n.66A>C | non_coding_transcript_exon_variant | 1/11 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251382Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135858
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GnomAD4 exome AF: 0.000109 AC: 159AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.000117 AC XY: 85AN XY: 727240
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 08, 2017 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 19, 2021 | Reported with a de novo missense variant on the opposite allele (in trans) in a male with features of a SPATA5-related disorder who underwent trio-based whole exome sequencing (Papuc et al., 2019); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30552426) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | AFG2A: PM2, PM3, PVS1:Moderate - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Pathogenic:1Uncertain:1
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | May 06, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change affects the initiator methionine of the SPATA5 mRNA. The next in-frame methionine is located at codon 75. This variant is present in population databases (rs552219028, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 30552426). ClinVar contains an entry for this variant (Variation ID: 203533). 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
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MutPred
Gain of glycosylation at S2 (P = 8e-04);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at