2-233309263-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting
The NM_000541.5(SAG):c.74C>T(p.Ser25Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,611,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S25S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000541.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SAG | NM_000541.5 | c.74C>T | p.Ser25Leu | missense_variant, splice_region_variant | 2/16 | ENST00000409110.6 | NP_000532.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SAG | ENST00000409110.6 | c.74C>T | p.Ser25Leu | missense_variant, splice_region_variant | 2/16 | 5 | NM_000541.5 | ENSP00000386444 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000316 AC: 48AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000197 AC: 49AN: 248784Hom.: 0 AF XY: 0.000178 AC XY: 24AN XY: 134968
GnomAD4 exome AF: 0.000181 AC: 264AN: 1459824Hom.: 0 Cov.: 29 AF XY: 0.000178 AC XY: 129AN XY: 726340
GnomAD4 genome AF: 0.000316 AC: 48AN: 152086Hom.: 0 Cov.: 32 AF XY: 0.000364 AC XY: 27AN XY: 74268
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 19, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 25 of the SAG protein (p.Ser25Leu). This variant is present in population databases (rs374930316, gnomAD 0.07%). This missense change has been observed in individual(s) with blindness (PMID: 32483926). ClinVar contains an entry for this variant (Variation ID: 972665). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
SAG-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 14, 2024 | The SAG c.74C>T variant is predicted to result in the amino acid substitution p.Ser25Leu. This variant was reported in an individual with visual impairment (Table S12; Diñeiro et al 2020. PubMed ID: 32483926). This variant is reported in 0.074% of alleles in individuals of Latino descent in gnomAD, which may be too common to be a primary cause of disease. Though we suspect this variant may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at