Genetic Variant SUMF1:p.Met1? (chr3-4467244-A-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_182760.4(SUMF1):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SUMF1
NM_182760.4 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.55

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: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 26 pathogenic variants. Next in-frame start position is after 91 codons. Genomic position: 4453049. Lost 0.241 part of the original CDS.

PS1

Another start lost variant in NM_182760.4 (SUMF1) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUMF1	NM_182760.4 link	c.2T>A	p.Met1?	start_lost	Exon 1 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.2T>A	p.Met1?	start_lost	Exon 1 of 9	1	NM_182760.4	ENSP00000272902.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723702

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33352

American (AMR)

AF:

0.00

AC:

AN:

44144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39440

South Asian (SAS)

AF:

0.00

AC:

AN:

84956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5436

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109710

Other (OTH)

AF:

0.00

AC:

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.59

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

T;.;T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.83

PhyloP100

3.5

PROVEAN

Benign

-0.86

N;N;N;N

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.93

P;.;D;.

Vest4

0.93

MutPred

1.0

Gain of ubiquitination at M1 (P = 0.017);Gain of ubiquitination at M1 (P = 0.017);Gain of ubiquitination at M1 (P = 0.017);Gain of ubiquitination at M1 (P = 0.017);

MVP

0.98

ClinPred

1.0

GERP RS

4.7

PromoterAI

-0.93

Under-expression

(source)

Varity_R

0.98

gMVP

0.81

Mutation Taster

=3/197

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over