rs200244203
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_StrongPS1_ModeratePM2PP5
The NM_018418.5(SPATA7):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000822 in 1,606,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_018418.5 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152216Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000470 AC: 11AN: 233902Hom.: 0 AF XY: 0.0000631 AC XY: 8AN XY: 126780
GnomAD4 exome AF: 0.0000859 AC: 125AN: 1454458Hom.: 0 Cov.: 31 AF XY: 0.0000927 AC XY: 67AN XY: 722734
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152216Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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Leber congenital amaurosis Pathogenic:1
Variant summary: SPATA7 c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met52) is located in exon 3 of the encoded protein. An activation of potential downstream translation initiation at this site would result in a shortened protein missing the first 51 amino acids from the protein sequence. Other presumably pathogenic truncating variants have been reported upstream of this alternate initiation codon in the HGMD or internal database (example, c.20_21delTC, p.Val7Glufs*16, c.136C>T, p.Gln46X). The variant allele was found at a frequency of 4.7e-05 in 233902 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPATA7 causing Leber Congenital Amaurosis (4.7e-05 vs 0.00087), allowing no conclusion about variant significance. c.3G>A has been reported in the literature in at least two compound heterozygous individuals affected with retinitis pigmentosa (e.g., Neveling_2012, Weisschuh_2024). These data indicate that the variant may 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: 24265693, 22334370, 37734845). ClinVar contains an entry for this variant (Variation ID: 844972). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Leber congenital amaurosis 3 Uncertain:1
This sequence change affects the initiator methionine of the SPATA7 mRNA. The next in-frame methionine is located at codon 52. This variant is present in population databases (rs200244203, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with retinitis pigmentosa (PMID: 22334370). ClinVar contains an entry for this variant (Variation ID: 844972). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at