3-4362153-A-G

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.1116T>C(p.Thr372Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,613,514 control chromosomes in the GnomAD database, including 284,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 35126 hom., cov: 34)

Exomes 𝑓: 0.58 ( 249772 hom. )

Consequence

SUMF1
NM_182760.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0940

Publications

29 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:

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 (BayesDel_noAF=-0.86).

BP6

Variant 3-4362153-A-G is Benign according to our data. Variant chr3-4362153-A-G is described in ClinVar as Benign. ClinVar VariationId is 96559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUMF1	NM_182760.4 link	c.1116T>C	p.Thr372Thr	synonymous_variant	Exon 9 of 9	ENST00000272902.10	NP_877437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUMF1	ENST00000272902.10 link	c.1116T>C	p.Thr372Thr	synonymous_variant	Exon 9 of 9	1	NM_182760.4	ENSP00000272902.5

Frequencies

GnomAD3 genomes

AF:

0.665

AC:

101084

AN:

152050

Hom.:

35060

Cov.:

show subpopulations

Gnomad AFR

AF:

0.858

Gnomad AMI

AF:

0.602

Gnomad AMR

AF:

0.691

Gnomad ASJ

AF:

0.625

Gnomad EAS

AF:

0.757

Gnomad SAS

AF:

0.753

Gnomad FIN

AF:

0.584

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.544

Gnomad OTH

AF:

0.664

GnomAD2 exomes

AF:

0.643

AC:

160356

AN:

249294

AF XY:

0.638

show subpopulations

Gnomad AFR exome

AF:

0.869

Gnomad AMR exome

AF:

0.744

Gnomad ASJ exome

AF:

0.608

Gnomad EAS exome

AF:

0.765

Gnomad FIN exome

AF:

0.577

Gnomad NFE exome

AF:

0.552

Gnomad OTH exome

AF:

0.611

GnomAD4 exome

AF:

0.578

AC:

845195

AN:

1461346

Hom.:

249772

Cov.:

AF XY:

0.582

AC XY:

422914

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.874

AC:

29274

AN:

33476

American (AMR)

AF:

0.731

AC:

32698

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.602

AC:

15723

AN:

26132

East Asian (EAS)

AF:

0.773

AC:

30684

AN:

39690

South Asian (SAS)

AF:

0.735

AC:

63424

AN:

86244

European-Finnish (FIN)

AF:

0.574

AC:

30643

AN:

53378

Middle Eastern (MID)

AF:

0.637

AC:

3645

AN:

5720

European-Non Finnish (NFE)

AF:

0.542

AC:

602644

AN:

1111606

Other (OTH)

AF:

0.604

AC:

36460

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

17853

35707

53560

71414

89267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17326

34652

51978

69304

86630

<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:

0.665

AC:

101212

AN:

152168

Hom.:

35126

Cov.:

AF XY:

0.670

AC XY:

49827

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.858

AC:

35652

AN:

41556

American (AMR)

AF:

0.691

AC:

10573

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.625

AC:

2169

AN:

3468

East Asian (EAS)

AF:

0.758

AC:

3911

AN:

5160

South Asian (SAS)

AF:

0.753

AC:

3631

AN:

4824

European-Finnish (FIN)

AF:

0.584

AC:

6176

AN:

10578

Middle Eastern (MID)

AF:

0.639

AC:

188

AN:

294

European-Non Finnish (NFE)

AF:

0.544

AC:

36951

AN:

67970

Other (OTH)

AF:

0.668

AC:

1413

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1660

3320

4979

6639

8299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.592

Hom.:

43556

Bravo

AF:

0.683

Asia WGS

AF:

0.781

AC:

2715

AN:

3478

EpiCase

AF:

0.557

EpiControl

AF:

0.565

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 26, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The SUMF1 c.1116T>C (p.Thr372Thr) variant involves the alteration of a non-conserved nucleotide causes a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. This variant was found in 176669/274930 control chromosomes (58685 homozygotes)(gnomAD) at a frequency of 0.6425963, which is approximately 575 times the estimated maximal expected allele frequency of a pathogenic SUMF1 variant (0.001118). The observed frequency the C allele, 0.64, indicates the variant of interest to be the major allele (allele more commonly observed in the general population). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Multiple sulfatase deficiency

Benign:5

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.8

(source)

DANN

Benign

0.45

PhyloP100

-0.094

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over