rs2819590

chr3-4467058-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182760.4(SUMF1):c.188G>A(p.Ser63Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,565,330 control chromosomes in the GnomAD database, including 60,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S63G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (3960 hom., cov: 32)
  • Exomes 𝑓: 0.27 (57014 hom.)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.519

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]

LOC124909340 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003894627).
• BP6: Variant 3-4467058-C-T is Benign according to our data. Variant chr3-4467058-C-T is described in ClinVar as [Benign]. Clinvar id is 263004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4467058-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUMF1	NM_182760.4	c.188G>A	p.Ser63Asn	missense_variant	1/9	ENST00000272902.10
LOC124909340	XR_007095789.1	n.235C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUMF1	ENST00000272902.10	c.188G>A	p.Ser63Asn	missense_variant	1/9	1	NM_182760.4	P1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30956 AN: 152060 Hom.: 3961 Cov.: 32

Gnomad AFR AF: 0.0739

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.216 AC: 37487 AN: 173514 Hom.: 4809 AF XY: 0.216 AC XY: 20539 AN XY: 95016

Gnomad AFR exome AF: 0.0642

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.00168

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.300

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.273 AC: 385976 AN: 1413152 Hom.: 57014 Cov.: 39 AF XY: 0.268 AC XY: 187410 AN XY: 698174

Gnomad4 AFR exome AF: 0.0620

Gnomad4 AMR exome AF: 0.201

Gnomad4 ASJ exome AF: 0.191

Gnomad4 EAS exome AF: 0.00162

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.203 AC: 30953 AN: 152178 Hom.: 3960 Cov.: 32 AF XY: 0.198 AC XY: 14743 AN XY: 74404

Gnomad4 AFR AF: 0.0736

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.276

Gnomad4 NFE AF: 0.294

Gnomad4 OTH AF: 0.194

Alfa AF: 0.260 Hom.: 3167

Bravo AF: 0.196

TwinsUK AF: 0.303 AC: 1123

ALSPAC AF: 0.308 AC: 1188

ESP6500AA AF: 0.0660 AC: 218

ESP6500EA AF: 0.253 AC: 1828

ExAC AF: 0.175 AC: 19802

Asia WGS AF: 0.0600 AC: 210 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple sulfatase deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2018	Variant summary: SUMF1 c.188G>A (p.Ser63Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.21 in 198742 control chromosomes in the gnomAD database, including 5502 homozygotes. The observed variant frequency is approximately 191 fold above the estimated maximal expected allele frequency for a pathogenic variant in SUMF1 causing Multiple Sulfatase Deficiency phenotype (0.0011), strongly suggesting that the variant is benign. Variant c.188G>A has been reported in individuals affected with Multiple Sulfatase Deficiency and authors listed the variant as a polymorphism (Dierks_2003). To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar and both classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;T;.
Eigen	Benign	0.087
Eigen_PC	Benign	0.059
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.69	T;T;T;T
MetaRNN	Benign	0.0039	T;T;T;T
MetaSVM	Benign	-1.3	T
MutationAssessor	Benign	1.6	L;L;.;L
MutationTaster	Benign	0.94	P;P;P;P;P
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.55	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.16	T;T;D;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.70	P;.;D;.
Vest4		0.31
MPC		0.14
ClinPred		0.067	T
GERP RS		3.0
Varity_R		0.075
gMVP		0.42

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: rs2819590; hg19: chr3-4508742; COSMIC: COSV55991494;