rs1064793391

Variant names:

• chr3-4417183-T-C
• rs1064793391
• NM_182760.4:c.785A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_182760.4(SUMF1):​c.785A>G​(p.Gln262Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q262Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 7.27
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_182760.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 3-4417183-T-C is Pathogenic according to our data. Variant chr3-4417183-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418724.

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.785A>G	p.Gln262Arg	missense	Exon 6 of 9	NP_877437.2
	SUMF1	NM_001164675.2		c.785A>G	p.Gln262Arg	missense	Exon 6 of 8	NP_001158147.1	Q8NBK3-5
	SUMF1	NM_001164674.2		c.710A>G	p.Gln237Arg	missense	Exon 5 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.785A>G	p.Gln262Arg	missense	Exon 6 of 9	ENSP00000272902.5	Q8NBK3-1
	SUMF1	ENST00000405420.2	TSL:1	c.785A>G	p.Gln262Arg	missense	Exon 6 of 8	ENSP00000384977.2	Q8NBK3-5
	SUMF1	ENST00000948922.1		c.806A>G	p.Gln269Arg	missense	Exon 6 of 9	ENSP00000618981.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	-	-	Multiple sulfatase deficiency (6)
-	1	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.043	D
Polyphen		0.98	D
Vest4		0.86
MutPred		0.71		Gain of MoRF binding (P = 0.0442)
MVP		0.91
MPC		0.48
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.94
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1064793391; hg19: chr3-4458867;