chr1-92832117-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_000969.5(RPL5):c.3G>A(p.Met1?) variant causes a start lost, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_000969.5 start_lost, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Diamond-Blackfan anemia Pathogenic:1
The p.M1? pathogenic mutation (also known as c.3G>A), located in coding exon 1 of the RPL5 gene, results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. In addition, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This mutation has been described in a Japanese individual with a clinical diagnosis of Diamond-Blackfan anemia (DBA), who had thumb polydactyly in addition to red blood cell aplasia (Konno Y et al. Haematologica 2010 Aug; 95(8):1293-9). Multiple other nucleotide substitutions that alter the initiation codon have also been reported in individuals with DBA (Konno Y et al. Haematologica 2010 Aug; 95(8):1293-9; Boria I et al. Hum. Mutat. 2010 Dec; 31(12):1269-79; Quarello P et al. Haematologica 2010 Feb; 95(2):206-13). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at