chr4-122934573-TCAA-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_145207.3(AFG2A):c.989_991delCAA(p.Thr330del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,613,642 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_145207.3 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152134Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000112 AC: 28AN: 249644Hom.: 1 AF XY: 0.000111 AC XY: 15AN XY: 135242
GnomAD4 exome AF: 0.000122 AC: 178AN: 1461508Hom.: 1 AF XY: 0.000127 AC XY: 92AN XY: 727034
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152134Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74314
ClinVar
Submissions by phenotype
Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Pathogenic:10
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (MIM#616577). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 29 heterozygotes, 1 homozygote). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (p.(Thr330Ala) - v2: 1 heterozygote, 0 homozygotes; p.(Thr330Arg) - v3: 1 heterozygote, 0 homozygotes). (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many affected individuals (PMIDs: 29343804, 34360601) and as pathogenic/likely pathogenic many times in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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This variant was identified as compound heterozygous with NM_145207.3:c.2166_2176del._x000D_ Criteria applied: PM3_VSTR, PM4 -
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Variant summary: AFG2A c.989_991delCAA (p.Thr330del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 0.00011 in 281030 control chromosomes in the gnomAD database, including 1 homozygotes. 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.989_991delCAA has been reported in the literature in multiple individuals affected with Epilepsy, Hearing Loss, And Mental Retardation Syndrome (example: Puusepp_2018, Papuc_2019, Braun_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: 29343804, 30552426, 34360601). ClinVar contains an entry for this variant (Variation ID: 207828). Based on the evidence outlined above, the variant was classified as pathogenic. -
This variant, c.989_991del, results in the deletion of 1 amino acid(s) of the SPATA5 protein (p.Thr330del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs748291365, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with epilepsy, hearing loss, and intellectual disability syndrome (PMID: 26299366, 27246907, 27683084, 28293831). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 207828). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:9
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The p.T330del variant in the SPATA5 gene was found in the homozygous state and has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The p.T330del variant results in the deletion of a single Threonine residue, denoted p.Thr330del, at a position that is conserved across species. The p.T330del variant was observed at an allele frequency of 0.0002 in approximately 33.000 individuals of European ancestry (ExAC database), indicating it is not a common benign variant in this population. However, in this database the variant is also present once in the homozygous state. Based on these data and because of highly similar clinical features between this patient and others with SPATA5 mutations we interpret the p.T330del variant as likely pathogenic. -
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In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26299366, 28293831, 27246907, 27683084, 29343804, 21822266, 30577886, 30552426, 30009132, 34426522, 33176815, 34360601, 31440721, 33177673, 38008000) -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at