rs1085307107

Positions:

• chr3-4452983-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_182760.4(SUMF1):​c.337G>A​(p.Glu113Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,810 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.49

Genes affected

SUMF1 (HGNC:20376): (sulfatase modifying factor 1) This gene encodes an enzyme that catalyzes the hydrolysis of sulfate esters by oxidizing a cysteine residue in the substrate sulfatase to an active site 3-oxoalanine residue, which is also known as C-alpha-formylglycine. Mutations in this gene cause multiple sulfatase deficiency, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 3-4452983-C-T is Pathogenic according to our data. Variant chr3-4452983-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUMF1	NM_182760.4	c.337G>A	p.Glu113Lys	missense_variant	2/9	ENST00000272902.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUMF1	ENST00000272902.10	c.337G>A	p.Glu113Lys	missense_variant	2/9	1	NM_182760.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple sulfatase deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	case-control	Children's Hospital DNA Laboratory, University Medical Center Goettingen	Apr 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	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. Experimental studies have shown that this missense change affects SUMF1 function (PMID: 28566233). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 225909). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 113 of the SUMF1 protein (p.Glu113Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple sulfatase deficiency (PMID: 28566233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2023

Published functional studies demonstrate a damaging effect on protein function (Jaszczuk et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21224894, 28566233) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.87
MutPred		0.75		Gain of ubiquitination at E113 (P = 0.0121);Gain of ubiquitination at E113 (P = 0.0121);Gain of ubiquitination at E113 (P = 0.0121);Gain of ubiquitination at E113 (P = 0.0121);
MVP		0.97
MPC		0.49
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1085307107; hg19: chr3-4494667;