rs137852849

chr3-4417132-G-Achr3-4417132-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_182760.4(SUMF1):c.836C>T(p.Ala279Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,613,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A279A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 9.08

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 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_182760.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-4417132-G-A is Pathogenic according to our data. Variant chr3-4417132-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2669.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.836C>T	p.Ala279Val	missense_variant	6/9	ENST00000272902.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUMF1	ENST00000272902.10	c.836C>T	p.Ala279Val	missense_variant	6/9	1	NM_182760.4	P1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251232 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135764

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000171 AC: 250 AN: 1461458 Hom.: 0 Cov.: 31 AF XY: 0.000150 AC XY: 109 AN XY: 727068

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74440

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000295 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple sulfatase deficiency Pathogenic:12 Other: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	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 16, 2003	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The SUMF1 c.836C>T p.Ala279Val variant is frequently observed in patients with multiple sulfatase deficiency (PMIDs:15146462; 12757706; 18157819; 12757705; 26825355; 25373814; 25885655). Functional studies of this variant show decreased stability and enzyme activity of the encoded protein (PMID:15146462; 18157819). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2021	Variant summary: SUMF1 c.836C>T (p.Ala279Val) results in a non-conservative amino acid change located in the Sulfatase-modifying factor enzyme domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251232 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SUMF1 causing Multiple Sulfatase Deficiency (9.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.836C>T has been reported in the literature in multiple individuals affected with Multiple Sulfatase Deficiency (example, Ahresn_2018, Dierks_2003, Miskin_2016, Prasad _2014, Sabourdy_2015). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in low enzyme activity across multiple sulfatases (example, Ahresn_2018, Miskin_2016, Sabourdy_2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus leaning towards a pathogenic/likely pathogenic outcome (VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 29, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jun 27, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 28, 2022	PS3, PS4_Supporting, PM2, PM3, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 279 of the SUMF1 protein (p.Ala279Val). This variant is present in population databases (rs137852849, gnomAD 0.02%). This missense change has been observed in individuals with multiple sulfatase deficiency (PMID: 12757705, 12757706, 15146462, 18157819, 25373814, 25885655). ClinVar contains an entry for this variant (Variation ID: 2669). 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 not expected to disrupt SUMF1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SUMF1 function (PMID: 18157819, 21224894). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 18, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2022	Published functional studies demonstrate that the variant results in severely decreased formylglycine-generating enzyme protein stability and severely impaired sulfatase-enhancing activity (Schlotawa et al., 2008; Cosma et al., 2004); 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: 29397290, 12757706, 25885655, 18157819, 21224894, 15146462, 19124046, 15907468, 29048999, 33643672, 12757705, 25373814, 26825355) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.7	L;.;L
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.88
MVP		0.94
MPC		0.42
ClinPred		0.24	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.89

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: rs137852849; hg19: chr3-4458816;