chr4-122947347-AATGCT-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_145207.3(SPATA5):βc.1574_1578delβ(p.Asn525ThrfsTer20) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000867 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000026 ( 0 hom., cov: 32)
Exomes π: 0.0000068 ( 0 hom. )
Consequence
SPATA5
NM_145207.3 frameshift
NM_145207.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.57
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-122947347-AATGCT-A is Pathogenic according to our data. Variant chr4-122947347-AATGCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 203529.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-122947347-AATGCT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPATA5 | NM_145207.3 | c.1574_1578del | p.Asn525ThrfsTer20 | frameshift_variant | 9/16 | ENST00000274008.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AFG2A | ENST00000274008.5 | c.1574_1578del | p.Asn525ThrfsTer20 | frameshift_variant | 9/16 | 1 | NM_145207.3 | P1 | |
AFG2A | ENST00000422835.2 | n.1616_1620del | non_coding_transcript_exon_variant | 9/15 | 1 | ||||
AFG2A | ENST00000675612.1 | c.1571_1575del | p.Asn524ThrfsTer20 | frameshift_variant | 9/17 | ||||
AFG2A | ENST00000674886.1 | n.1636_1640del | non_coding_transcript_exon_variant | 9/11 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251438Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135888
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461838Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 727222
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74324
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 03, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2021 | This sequence change creates a premature translational stop signal (p.Asn525Thrfs*20) in the SPATA5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPATA5 are known to be pathogenic (PMID: 26299366). This variant is present in population databases (rs796051891, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with epilepsy, hearing loss, and mental retardation syndrome (PMID: 26299366). ClinVar contains an entry for this variant (Variation ID: 203529). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at