rs775112689
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000199.5(SGSH):c.416C>T(p.Thr139Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T139S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000199.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGSH | NM_000199.5 | c.416C>T | p.Thr139Met | missense_variant | 4/8 | ENST00000326317.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGSH | ENST00000326317.11 | c.416C>T | p.Thr139Met | missense_variant | 4/8 | 1 | NM_000199.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250682Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135794
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1460780Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726694
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Pathogenic:3Uncertain:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.T139M in SGSH (NM_000199.5) has been submitted previously to ClinVar with conflicting interpretations of pathogenicity (Likely Pathogenic/ Uncertain Significance). No details for independent assesment are available for the Likely Pathogenic classification. It has not been reported previously in affected individuals to the best of our knowledge. The p.T139M variant is observed in 1/16,194 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.T139M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 139 of SGSH is conserved in all mammalian species. The nucleotide c.416 in SGSH is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 20, 2023 | - - |
Pathogenic, no assertion criteria provided | research | Section for Clinical Neurogenetics, University of Tübingen | Aug 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 02, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 139 of the SGSH protein (p.Thr139Met). This variant is present in population databases (rs775112689, gnomAD 0.004%). This missense change has been observed in individual(s) with Sanfilippo syndrome (PMID: 9285796, 24576347). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551670). 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: "Probably Damaging"; 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2021 | NM_000199.3(SGSH):c.416C>T(T139M) is a missense variant classified as a variant of uncertain significance in the context of mucopolysaccharidosis type IIIA. T139M has been observed in cases with relevant disease (PMID: 9285796; 24576347). Functional assessments of this variant are not available in the literature. T139M has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000199.3(SGSH):c.416C>T(T139M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 25, 2021 | The variant chr17-78188504-G-A, SGSH(NM_000199.5):c.416C>T,p.(Thr139Met) was identified in an individual with NDD. Inheritance was not applicable (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Likely Pathogenic (criteria: PM2_Supporting, PM3_Strong, PP3_Supporting, PP4_Supporting). This variant was identified in a compound heterozygous state with the variantNM_000199.5(SGSH):c.267C>A (p.Tyr89Ter) ( Variation ID: 983123). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at