rs200142963

chr3-4467188-G-Achr3-4467188-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

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. 12/21 in silico tools predict 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

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06518516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUMF1	NM_182760.4	c.58C>T	p.Leu20Phe	missense_variant	1/9	ENST00000272902.10
LOC124909340	XR_007095789.1	n.365G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUMF1	ENST00000272902.10	c.58C>T	p.Leu20Phe	missense_variant	1/9	1	NM_182760.4	P1

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

GnomAD3 exomes AF: 0.0000623 AC: 15 AN: 240854 Hom.: 0 AF XY: 0.0000686 AC XY: 9 AN XY: 131150

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 SAS 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

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000729

Gnomad4 OTH exome AF: 0.0000831

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

Gnomad4 AFR AF: 0.000169

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: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000477 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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 13, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2017	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 28, 2023

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 v4.3

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;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.61	T;T;T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.065	T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.90	L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.38	N;N;N;N
REVEL	Uncertain	0.53
Sift	Benign	0.52	T;T;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.28
MVP		0.39
MPC		0.091
ClinPred		0.016	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.039
gMVP		0.64

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: rs200142963; hg19: chr3-4508872;