chr2-233309263-C-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000541.5(SAG):c.74C>A(p.Ser25Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,611,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S25S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000541.5 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SAG | NM_000541.5 | c.74C>A | p.Ser25Ter | stop_gained, splice_region_variant | 2/16 | ENST00000409110.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SAG | ENST00000409110.6 | c.74C>A | p.Ser25Ter | stop_gained, splice_region_variant | 2/16 | 5 | NM_000541.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248784Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134968
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1459828Hom.: 0 Cov.: 29 AF XY: 0.00000688 AC XY: 5AN XY: 726340
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74268
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with SAG-related conditions. This variant is present in population databases (rs374930316, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Ser25*) in the SAG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SAG are known to be pathogenic (PMID: 9452120, 15234147, 22665972). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at