Genetic Variant NM_182760.4:c.188G>T (chr3-4467058-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_182760.4(SUMF1):c.188G>T(p.Ser63Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,413,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S63N) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SUMF1
NM_182760.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.519

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3510297).

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>T	p.Ser63Ile	missense	Exon 1 of 9	NP_877437.2
SUMF1	NM_001164675.2		c.188G>T	p.Ser63Ile	missense	Exon 1 of 8	NP_001158147.1
SUMF1	NM_001164674.2		c.188G>T	p.Ser63Ile	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>T	p.Ser63Ile	missense	Exon 1 of 9	ENSP00000272902.5
SUMF1	ENST00000405420.2	TSL:1	c.188G>T	p.Ser63Ile	missense	Exon 1 of 8	ENSP00000384977.2
SUMF1	ENST00000383843.9	TSL:2	c.188G>T	p.Ser63Ile	missense	Exon 1 of 8	ENSP00000373355.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1413338

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32318

American (AMR)

AF:

0.00

AC:

AN:

37668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25360

East Asian (EAS)

AF:

0.00

AC:

AN:

37002

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4402

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087954

Other (OTH)

AF:

0.00

AC:

AN:

58362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.35

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

1.6

PhyloP100

0.52

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.38

Sift

Benign

0.052

Sift4G

Benign

0.16

Polyphen

0.94

Vest4

0.40

MutPred

0.28

Loss of glycosylation at S63 (P = 0.0046)

MVP

0.94

MPC

0.21

ClinPred

0.87

GERP RS

3.0

PromoterAI

0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.59

Mutation Taster

=85/15

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over