rs202150579
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000199.5(SGSH):c.1076C>T(p.Ala359Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000199.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152238Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000801 AC: 20AN: 249546Hom.: 0 AF XY: 0.0000666 AC XY: 9AN XY: 135164
GnomAD4 exome AF: 0.0000329 AC: 48AN: 1460406Hom.: 0 Cov.: 34 AF XY: 0.0000275 AC XY: 20AN XY: 726468
GnomAD4 genome AF: 0.000203 AC: 31AN: 152356Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74504
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Uncertain:4
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 359 of the SGSH protein (p.Ala359Val). This variant is present in population databases (rs202150579, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with SGSH-related conditions. ClinVar contains an entry for this variant (Variation ID: 325834). 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 tolerated. 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. -
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Uncertain:3
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BP4 -
Inborn genetic diseases Uncertain:1
The c.1076C>T (p.A359V) alteration is located in exon 8 (coding exon 8) of the SGSH gene. This alteration results from a C to T substitution at nucleotide position 1076, causing the alanine (A) at amino acid position 359 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at