rs1554498242
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_152415.3(VPS37A):c.1145A>C(p.Lys382Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. K382N) has been classified as Pathogenic.
Frequency
Consequence
NM_152415.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS37A | NM_152415.3 | c.1145A>C | p.Lys382Thr | missense_variant | 11/12 | ENST00000324849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS37A | ENST00000324849.9 | c.1145A>C | p.Lys382Thr | missense_variant | 11/12 | 1 | NM_152415.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461558Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727054
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 53 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 09, 2016 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VPS37A-related disease. This sequence change replaces lysine with threonine at codon 382 of the VPS37A protein (p.Lys382Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. A different missense substitution at this codon (p.Lys382Asn) has been reported in affected individuals (PMID: 22717650), but the clinical significance of this finding is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at