chr2-3575351-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001011.4(RPS7):c.-19+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_001011.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 0
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Diamond-Blackfan anemia 8 Pathogenic:2
The heterozygous c.-19+1G>A variant in RPS7 was identified by our study in one individual with Diamond-Blackfan anemia. The c.-19+1G>A variant in RPS7 has not been previously reported in individuals with Diamond-Blackfan anemia 8. This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 975849) and has been interpreted as pathogenic by the Stanford Medicine Clinical Genomics Program. This variant was found de novo in one individual with confirmed paternity and maternity (ClinVar Variation ID: 975849). A different nucleotide change at the same site (i.e., the 5’-UTR splice-site of the RPS7 first exon), c.-19+1G>T (PMID: 36057918) has been previously reported pathogenic, and the variant being assessed here, c.-19+1G>A, is predicted by SpliceAI to have a similar effect on splicing. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Heterozygous loss of function of the RPS7 gene is an established disease mechanism in Diamond-Blackfan anemia 8. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Diamond-Blackfan anemia 8. ACMG/AMP Criteria applied: PVS1_Strong, PS1_Supporting, PS2_Moderate, PM2_Supporting (Richards 2015). -
The c.-19+1G>A variant in the RPS7 gene was identified de novo in this individual, but has not been previously reported in association with disease and was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant alters the canonical donor splice site in intron 1, which is predicted to result in abnormal gene splicing. Heterozygous loss of function is an established mechanism of disease for the RPS7 gene. Notably, different nucleotide changes (c.-19+1G>C, c.- 19+1G>T, c.-19+2T>C) disrupting the same canonical splice site have been previously reported (Smetanina et al., 2015; van Dooijeweert et al., 2018). These reported disease-causing variant are expected to result in a similar disruption to protein function as c.-19+1G>A. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.-19+1G>A variant as pathogenic for autosomal dominant Diamond-Blackfan anemia based on the information above. [ACMG evidence codes used: PVS1_Strong; PS2; PM2] -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at