3-4467058-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S63G) has been classified as Uncertain significance.

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

Publications

26 publications found

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 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

SUMF1 links:

LOC124909340 (HGNC:):

LOC124909340 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 263004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SUMF1	NM_182760.4	MANE Select	c.188G>A	p.Ser63Asn	missense	Exon 1 of 9	NP_877437.2
SUMF1	NM_001164675.2		c.188G>A	p.Ser63Asn	missense	Exon 1 of 8	NP_001158147.1
SUMF1	NM_001164674.2		c.188G>A	p.Ser63Asn	missense	Exon 1 of 8	NP_001158146.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SUMF1	ENST00000272902.10	TSL:1 MANE Select	c.188G>A	p.Ser63Asn	missense	Exon 1 of 9	ENSP00000272902.5
SUMF1	ENST00000405420.2	TSL:1	c.188G>A	p.Ser63Asn	missense	Exon 1 of 8	ENSP00000384977.2
SUMF1	ENST00000948922.1		c.188G>A	p.Ser63Asn	missense	Exon 1 of 9	ENSP00000618981.1

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

GnomAD2 exomes

AF:

0.216

AC:

37487

AN:

173514

AF XY:

0.216

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 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

African (AFR)

AF:

0.0620

AC:

2004

AN:

32316

American (AMR)

AF:

0.201

AC:

7579

AN:

37660

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

4842

AN:

25360

East Asian (EAS)

AF:

0.00162

AC:

AN:

37002

South Asian (SAS)

AF:

0.123

AC:

9973

AN:

81202

European-Finnish (FIN)

AF:

0.275

AC:

13475

AN:

49054

Middle Eastern (MID)

AF:

0.153

AC:

675

AN:

4402

European-Non Finnish (NFE)

AF:

0.306

AC:

333367

AN:

1087796

Other (OTH)

AF:

0.240

AC:

14001

AN:

58360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

18647

37293

55940

74586

93233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10742

21484

32226

42968

53710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.203

AC:

30953

AN:

152178

Hom.:

3960

Cov.:

AF XY:

0.198

AC XY:

14743

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0736

AC:

3058

AN:

41544

American (AMR)

AF:

0.201

AC:

3081

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.199

AC:

688

AN:

3466

East Asian (EAS)

AF:

0.00329

AC:

AN:

5174

South Asian (SAS)

AF:

0.112

AC:

537

AN:

4816

European-Finnish (FIN)

AF:

0.276

AC:

2926

AN:

10604

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.294

AC:

19989

AN:

67946

Other (OTH)

AF:

0.194

AC:

411

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1179

2357

3536

4714

5893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

324

648

972

1296

1620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.259

Hom.:

3576

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Multiple sulfatase deficiency (4)

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

0.087

Eigen_PC

Benign

0.059

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.3

MutationAssessor

Benign

1.6

PhyloP100

0.52

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.55

REVEL

Benign

0.24

Sift

Benign

0.16

Sift4G

Benign

0.42

Polyphen

0.70

Vest4

0.31

MPC

0.14

ClinPred

0.067

GERP RS

3.0

PromoterAI

0.0041

Neutral

(source)

Varity_R

0.075

gMVP

0.42

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over