chr3-4418082-C-T

Position:

• chr3-4418082-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_182760.4(SUMF1):​c.653G>A​(p.Cys218Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,778 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C218C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.17

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 16 ACMG points.

• PM1: In a disulfide_bond (size 147) in uniprot entity SUMF1_HUMAN there are 23 pathogenic changes around while only 2 benign (92%) in NM_182760.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 3-4418082-C-T is Pathogenic according to our data. Variant chr3-4418082-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2677.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.653G>A	p.Cys218Tyr	missense_variant	5/9	ENST00000272902.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUMF1	ENST00000272902.10	c.653G>A	p.Cys218Tyr	missense_variant	5/9	1	NM_182760.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251368 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple sulfatase deficiency Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2023	Variant summary: SUMF1 c.653G>A (p.Cys218Tyr) results in a non-conservative amino acid change located in the Sulfatase-modifying factor enzyme (IPR005532) of the encoded protein sequence, and Cys218 has been suggested to be involved in SUMF1 protein stability (Dierks_2005). 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 8e-06 in 251368 control chromosomes. c.653G>A has been reported at a compound heterozygous state along with a pathogenic missense variant in at-least one individual affected with Multiple Sulfatase Deficiency (example, Cosma_2003). At least one publication reports experimental evidence evaluating an impact on protein function (Cosma_2003). The most pronounced variant effect results in <10% of normal activity in fibroblasts from the patient of multiple sulfatase deficiency, carrying p.Cys218Tyr and p.Arg345Cys at a compound heterozygous state, in whom p.Arg345Cys has shown to significantly compromised sulfatase activities (PMID: 21224894). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12757706, 15907468). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2023	Experimental studies have shown that this missense change affects SUMF1 function (PMID: 15146462). 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. 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. ClinVar contains an entry for this variant (Variation ID: 2677). This missense change has been observed in individual(s) with multiple sulfatase deficiency (MSD) (PMID: 15146462). This variant is present in population databases (rs137852854, gnomAD 0.003%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 218 of the SUMF1 protein (p.Cys218Tyr). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 16, 2003	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;.;H
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.94		Gain of ubiquitination at K223 (P = 0.115);.;Gain of ubiquitination at K223 (P = 0.115);
MVP		0.96
MPC		0.60
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97

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: rs137852854; hg19: chr3-4459766;