rs137852850
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_182760.4(SUMF1):āc.463T>Cā(p.Ser155Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,052 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S155F) has been classified as Uncertain significance.
Frequency
Consequence
NM_182760.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUMF1 | NM_182760.4 | c.463T>C | p.Ser155Pro | missense_variant | 3/9 | ENST00000272902.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUMF1 | ENST00000272902.10 | c.463T>C | p.Ser155Pro | missense_variant | 3/9 | 1 | NM_182760.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251440Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135888
GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461824Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39AN XY: 727208
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74370
ClinVar
Submissions by phenotype
Multiple sulfatase deficiency Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2011 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 02, 2017 | Variant summary: The SUMF1 c.463T>C (p.Ser155Pro) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 5/121384 control chromosomes at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic SUMF1 variant (0.001118). The variant was reported in numerous affected individuals in the literature in both the homozygous and compound heterozygous state, and functional evidence has showed patients have a drastic reduction in sulfatase activity compared to wild-type. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 155 of the SUMF1 protein (p.Ser155Pro). This variant is present in population databases (rs137852850, gnomAD 0.2%). This missense change has been observed in individual(s) with multiple sulfatase deficiency (PMID: 12757706, 16125993, 21224894, 25885655, 27344646). ClinVar contains an entry for this variant (Variation ID: 2672). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SUMF1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SUMF1 function (PMID: 15146462, 17657823, 21224894). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | SUMF1: PM3:Strong, PM2, PM5, PP4, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2022 | Published functional studies demonstrate a damaging effect with impaired enzymatic activity compared to wildtype (Cosma et al., 2004; Shlotawa et al., 2011); This variant is associated with the following publications: (PMID: 18305113, 29479672, 29048999, 21224894, 12757706, 15146462, 29972788, 29899769, 27344646, 31980526, 31589614) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 30, 2019 | PS3, PS4_moderate, PM2, PP4, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 18, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at