3-4362223-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_182760.4(SUMF1):c.1046G>A(p.Arg349Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R349P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SUMF1
NM_182760.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.00

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_182760.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-4362223-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2734439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 3-4362223-C-T is Pathogenic according to our data. Variant chr3-4362223-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUMF1	NM_182760.4 linkuse as main transcript	c.1046G>A	p.Arg349Gln	missense_variant	9/9	ENST00000272902.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUMF1	ENST00000272902.10 linkuse as main transcript	c.1046G>A	p.Arg349Gln	missense_variant	9/9	1	NM_182760.4	P1	Q8NBK3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248998

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134808

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000993

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple sulfatase deficiency

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 09, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg349 amino acid residue in SUMF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12757706, 15146462, 25373814). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SUMF1 protein function. ClinVar contains an entry for this variant (Variation ID: 2667). This missense change has been observed in individual(s) with multiple sulfatase deficiency (PMID: 12757705). This variant is present in population databases (rs137852847, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 349 of the SUMF1 protein (p.Arg349Gln). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 16, 2003	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 02, 2022

Published functional studies demonstrate a damaging effect showing reduced activation of sulfatases ARSA, ARSC, and ARSE compared to wild type SUMF1 (Cosma et al., 2004); Identified in a patient with severe multiple sulphatase deficiency in published literature (Cosma et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12757706, 24484558, 28452122, 31589614, 15146462, 12757705, 18157819, 29048999, 25373814) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

H;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.94

MutPred

0.97

Loss of MoRF binding (P = 0.0171);.;.;.;

MVP

0.94

MPC

0.50

ClinPred

1.0

GERP RS

6.0

Varity_R

0.91

gMVP

0.94

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