rs200142963

Variant names:

• chr3-4467188-G-A
• rs200142963
• NM_182760.4:c.58C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-4467188-G-A
• chr3-4467188-G-C
• chr3-4467188-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_182760.4(SUMF1):​c.58C>T​(p.Leu20Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000733 in 1,610,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L20R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: -0.137
• Publications: 3 publications found

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]

SUMF1 Gene-Disease associations (from GenCC):

• mucosulfatidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P

LOC124909340 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 3-4467188-G-A is Pathogenic according to our data. Variant chr3-4467188-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552721.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06518516). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182760.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMF1	NM_182760.4	MANE Select	c.58C>T	p.Leu20Phe	missense	Exon 1 of 9	NP_877437.2
	SUMF1	NM_001164675.2		c.58C>T	p.Leu20Phe	missense	Exon 1 of 8	NP_001158147.1
	SUMF1	NM_001164674.2		c.58C>T	p.Leu20Phe	missense	Exon 1 of 8	NP_001158146.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMF1	ENST00000272902.10	TSL:1 MANE Select	c.58C>T	p.Leu20Phe	missense	Exon 1 of 9	ENSP00000272902.5
	SUMF1	ENST00000405420.2	TSL:1	c.58C>T	p.Leu20Phe	missense	Exon 1 of 8	ENSP00000384977.2
	SUMF1	ENST00000383843.9	TSL:2	c.58C>T	p.Leu20Phe	missense	Exon 1 of 8	ENSP00000373355.5

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000623 AC: 15 AN: 240854 AF XY: 0.0000686

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000837

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000672 AC: 98 AN: 1458374 Hom.: 0 Cov.: 34 AF XY: 0.0000717 AC XY: 52 AN XY: 725292

African (AFR) AF: 0.000270 AC: 9 AN: 33370

American (AMR) AF: 0.0000450 AC: 2 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 85644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5282

European-Non Finnish (NFE) AF: 0.0000729 AC: 81 AN: 1110994

Other (OTH) AF: 0.0000831 AC: 5 AN: 60160

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74356

African (AFR) AF: 0.000169 AC: 7 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000802 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple sulfatase deficiency Uncertain:2

Jul 05, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 20 of the SUMF1 protein (p.Leu20Phe). This variant is present in population databases (rs200142963, gnomAD 0.03%). This missense change has been observed in individual(s) with multiple sulfatase deficiency or clinical suspicion of lysosomal storage disease (PMID: 15146462, 30548430). ClinVar contains an entry for this variant (Variation ID: 552721). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SUMF1 function (PMID: 15146462). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided Pathogenic:1

Feb 27, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with significantly reduced enzyme activity of multiple sulfatases (Cosma MP et al., 2004); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17657823, 26123021, 15146462, 30548430, 32620537, 19124046, 29431110)

not specified Uncertain:1

Mar 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SUMF1 c.58C>T (p.Leu20Phe) results in a non-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 6.2e-05 in 240854 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SUMF1 causing Multiple Sulfatase Deficiency (6.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.58C>T has been reported in the literature in an individual with clinical features of Multiple Sulfatase Deficiency (example: Cosma_2004). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in approximately 40% of normal activity (example: Cosma_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	1.5
DANN	Benign	0.87
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.14
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.53
Sift	Benign	0.52	T
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.28
MVP		0.39
MPC		0.091
ClinPred		0.016	T
GERP RS		-1.8
PromoterAI		0.056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.039
gMVP		0.64
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs200142963; hg19: chr3-4508872;