3-4362236-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_182760.4(SUMF1):c.1033C>T(p.Arg345Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,004 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R345H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_182760.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SUMF1 | NM_182760.4 | c.1033C>T | p.Arg345Cys | missense_variant | 9/9 | ENST00000272902.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SUMF1 | ENST00000272902.10 | c.1033C>T | p.Arg345Cys | missense_variant | 9/9 | 1 | NM_182760.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248914Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134764
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461804Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727216
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Multiple sulfatase deficiency Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 345 of the SUMF1 protein (p.Arg345Cys). This variant is present in population databases (rs137852852, gnomAD 0.01%). This missense change has been observed in individual(s) with multiple sulfatase deficiency (PMID: 12757706, 21224894). ClinVar contains an entry for this variant (Variation ID: 2675). 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: 21224894). For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Feb 14, 2023 | The missense c.1033C>T(p.Arg345Cys) variant in SUMF1 gene has been reported in homozygous state in multiple individual affected with multiple sulfatase deficiency (Schlotawa L, et. al., 2011; Cosma MP, et. al., 2003). Experimental studies have shown disruption of protein (Schlotawa L, et. al., 2011). The variant is reported with an allele frequency of 0.0004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg345Cys in SUMF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 345 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 11, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at