rs137852853

Variant names:

• chr3-4362227-C-A
• rs137852853
• NM_182760.4:c.1042G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-4362227-C-A
• chr3-4362227-C-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM1 PM2 PM5 PP5_Moderate

The NM_182760.4(SUMF1):​c.1042G>T​(p.Ala348Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005184712: different missense changes affecting the same amino acid (A348P/V) have been reported in affected individuals (HGMD) and been demonstrated to result in severely impaired sulfatase-enhancing activity in in vitro functional studies (PMIDs 32048457, 12757706), indicating that this residue is critical for protein function.". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A348P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.32
• Publications: 0 publications found

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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005184712: different missense changes affecting the same amino acid (A348P/V) have been reported in affected individuals (HGMD) and been demonstrated to result in severely impaired sulfatase-enhancing activity in in vitro functional studies (PMIDs 32048457, 12757706), indicating that this residue is critical for protein function.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr3-4362227-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 3-4362227-C-A is Pathogenic according to our data. Variant chr3-4362227-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3335973.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMF1	NM_182760.4	MANE Select	c.1042G>T	p.Ala348Ser	missense	Exon 9 of 9	NP_877437.2
	SUMF1	NM_001164675.2		c.982G>T	p.Ala328Ser	missense	Exon 8 of 8	NP_001158147.1	Q8NBK3-5
	SUMF1	NM_001164674.2		c.967G>T	p.Ala323Ser	missense	Exon 8 of 8	NP_001158146.1	Q8NBK3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMF1	ENST00000272902.10	TSL:1 MANE Select	c.1042G>T	p.Ala348Ser	missense	Exon 9 of 9	ENSP00000272902.5	Q8NBK3-1
	SUMF1	ENST00000405420.2	TSL:1	c.982G>T	p.Ala328Ser	missense	Exon 8 of 8	ENSP00000384977.2	Q8NBK3-5
	SUMF1	ENST00000948922.1		c.1063G>T	p.Ala355Ser	missense	Exon 9 of 9	ENSP00000618981.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple sulfatase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.019	D
Polyphen		0.98	D
Vest4		0.61
MutPred		0.56		Gain of phosphorylation at A348 (P = 0.0187)
MVP		0.88
MPC		0.44
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.50
gMVP		0.65
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs137852853; hg19: chr3-4403911;