rs2633851

Positions:

• chr3-4362133-T-A
• chr3-4362133-T-C
• chr3-4362133-T-G

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.*11A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 1,611,076 control chromosomes in the GnomAD database, including 276,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31464 hom., cov: 33)
  • Exomes 𝑓: 0.57 (245449 hom.)
• Consequence: SUMF1 NM_182760.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.812

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-4362133-T-A is Benign according to our data. Variant chr3-4362133-T-A is described in ClinVar as [Benign]. Clinvar id is 96558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4362133-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUMF1	NM_182760.4	c.*11A>T		3_prime_UTR_variant	9/9	ENST00000272902.10	NP_877437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUMF1	ENST00000272902.10	c.*11A>T		3_prime_UTR_variant	9/9	1	NM_182760.4	ENSP00000272902	P1

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96440 AN: 151888 Hom.: 31421 Cov.: 33

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.641

GnomAD3 exomes AF: 0.634 AC: 158118 AN: 249370 Hom.: 51402 AF XY: 0.631 AC XY: 85074 AN XY: 134910

Gnomad AFR exome AF: 0.770

Gnomad AMR exome AF: 0.738

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.764

Gnomad SAS exome AF: 0.734

Gnomad FIN exome AF: 0.576

Gnomad NFE exome AF: 0.550

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.575 AC: 838431 AN: 1459070 Hom.: 245449 Cov.: 34 AF XY: 0.578 AC XY: 419951 AN XY: 725950

Gnomad4 AFR exome AF: 0.769

Gnomad4 AMR exome AF: 0.725

Gnomad4 ASJ exome AF: 0.595

Gnomad4 EAS exome AF: 0.773

Gnomad4 SAS exome AF: 0.735

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.541

Gnomad4 OTH exome AF: 0.596

GnomAD4 genome AF: 0.635 AC: 96534 AN: 152006 Hom.: 31464 Cov.: 33 AF XY: 0.641 AC XY: 47628 AN XY: 74300

Gnomad4 AFR AF: 0.758

Gnomad4 AMR AF: 0.678

Gnomad4 ASJ AF: 0.619

Gnomad4 EAS AF: 0.758

Gnomad4 SAS AF: 0.751

Gnomad4 FIN AF: 0.582

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.645

Alfa AF: 0.497 Hom.: 2497

Bravo AF: 0.649

Asia WGS AF: 0.770 AC: 2679 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 26, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Multiple sulfatase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.4
DANN	Benign	0.58

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: rs2633851; hg19: chr3-4403817; COSMIC: COSV55991857;