chr20-761166-G-A
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_033409.4(SLC52A3):c.1270C>T(p.Leu424Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,577,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L424L) has been classified as Likely benign.
Frequency
Consequence
NM_033409.4 missense
Scores
Clinical Significance
Conservation
Publications
- Brown-Vialetto-van Laere syndrome 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
- progressive bulbar palsyInheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152262Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000109 AC: 2AN: 184004 AF XY: 0.0000100 show subpopulations
GnomAD4 exome AF: 0.0000316 AC: 45AN: 1425222Hom.: 0 Cov.: 30 AF XY: 0.0000340 AC XY: 24AN XY: 705762 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74392 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.1270C>T (p.L424F) alteration is located in exon 5 (coding exon 4) of the SLC52A3 gene. This alteration results from a C to T substitution at nucleotide position 1270, causing the leucine (L) at amino acid position 424 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Brown-Vialetto-van Laere syndrome 1 Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 424 of the SLC52A3 protein (p.Leu424Phe). This variant is present in population databases (rs369230517, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SLC52A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 476599). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at