15-44633621-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_025137.4(SPG11):c.1619G>A(p.Arg540His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R540C) has been classified as Uncertain significance.
Frequency
Consequence
NM_025137.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPG11 | NM_025137.4 | c.1619G>A | p.Arg540His | missense_variant | 8/40 | ENST00000261866.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPG11 | ENST00000261866.12 | c.1619G>A | p.Arg540His | missense_variant | 8/40 | 1 | NM_025137.4 |
Frequencies
GnomAD3 genomes AF: 0.0000330 AC: 5AN: 151682Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250454Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135494
GnomAD4 exome AF: 0.0000411 AC: 60AN: 1461388Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 726962
GnomAD4 genome AF: 0.0000330 AC: 5AN: 151682Hom.: 0 Cov.: 31 AF XY: 0.0000405 AC XY: 3AN XY: 74062
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2020 | The p.R540H variant (also known as c.1619G>A), located in coding exon 8 of the SPG11 gene, results from a G to A substitution at nucleotide position 1619. The arginine at codon 540 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hereditary spastic paraplegia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 540 of the SPG11 protein (p.Arg540His). This variant is present in population databases (rs750200448, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 582680). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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