14-88385821-G-A
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_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
Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000086 ( 0 hom. )
Consequence
SPATA7
NM_018418.5 start_lost
NM_018418.5 start_lost
Scores
4
5
5
Clinical Significance
Conservation
PhyloP100: 3.71
Genes affected
SPATA7 (HGNC:20423): (spermatogenesis associated 7) This gene, originally isolated from testis, is also expressed in retina. Mutations in this gene are associated with Leber congenital amaurosis and juvenile retinitis pigmentosa. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]
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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_018418.5 (SPATA7) was described as [Likely_pathogenic] in ClinVar as 1704585
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-88385821-G-A is Pathogenic according to our data. Variant chr14-88385821-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 844972.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr14-88385821-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPATA7 | NM_018418.5 | c.3G>A | p.Met1? | start_lost | 1/12 | ENST00000393545.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPATA7 | ENST00000393545.9 | c.3G>A | p.Met1? | start_lost | 1/12 | 1 | NM_018418.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152216Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000470 AC: 11AN: 233902Hom.: 0 AF XY: 0.0000631 AC XY: 8AN XY: 126780
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
Leber congenital amaurosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 07, 2023 | 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. Other presumably pathogenic truncating variants have been reported upstream of this alternate codon in the HGMD database (example, c.20_21delTC, p.Val7Glufs*16). Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 233902 control chromosomes (gnomAD). This frequency is not significantly higher than expected 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 one compound heterozygous individual affected with Retinitis Pigmentosa (Neveling_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and one as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Leber congenital amaurosis 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Benign
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Benign
T;T;T;.;T;T
Polyphen
D;B;D;.;.;.
Vest4
MutPred
Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);Loss of methylation at R6 (P = 0.066);
MVP
ClinPred
D
GERP RS
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