3-4467058-C-T

Position:

chr3-4467058-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.20 ( 3960 hom., cov: 32)

Exomes 𝑓: 0.27 ( 57014 hom. )

Consequence

SUMF1
NM_182760.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.519

Variant links:

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 links:

SUMF1 (HGNC:):

SUMF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
SUMF1	NM_182760.4 linkuse as main transcript	c.188G>A	p.Ser63Asn	missense_variant	1/9	ENST00000272902.10	NP_877437.2	Q8NBK3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUMF1	ENST00000272902.10 linkuse as main transcript	c.188G>A	p.Ser63Asn	missense_variant	1/9	1	NM_182760.4	ENSP00000272902.5		Q8NBK3-1

Frequencies

GnomAD3 genomes

AF:

0.204

AC:

30956

AN:

152060

Hom.:

3961

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.268

AC XY:

187410

AN XY:

698174

show subpopulations

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.:

AF XY:

0.198

AC XY:

14743

AN XY:

74404

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple sulfatase deficiency

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.;T;.

Eigen

Benign

0.087

Eigen_PC

Benign

0.059

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.69

T;T;T;T

MetaRNN

Benign

0.0039

T;T;T;T

MetaSVM

Benign

-1.3

MutationAssessor

Benign

1.6

L;L;.;L

PrimateAI

Pathogenic

0.83

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over