3-4417132-G-C

Variant names:

• chr3-4417132-G-C
• rs137852849
• NM_182760.4:c.836C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_182760.4(SUMF1):​c.836C>G​(p.Ala279Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A279V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.08
• Publications: 24 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, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-4417132-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMF1	NM_182760.4	MANE Select	c.836C>G	p.Ala279Gly	missense	Exon 6 of 9	NP_877437.2
	SUMF1	NM_001164675.2		c.836C>G	p.Ala279Gly	missense	Exon 6 of 8	NP_001158147.1
	SUMF1	NM_001164674.2		c.761C>G	p.Ala254Gly	missense	Exon 5 of 8	NP_001158146.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMF1	ENST00000272902.10	TSL:1 MANE Select	c.836C>G	p.Ala279Gly	missense	Exon 6 of 9	ENSP00000272902.5
	SUMF1	ENST00000405420.2	TSL:1	c.836C>G	p.Ala279Gly	missense	Exon 6 of 8	ENSP00000384977.2
	SUMF1	ENST00000383843.9	TSL:2	c.761C>G	p.Ala254Gly	missense	Exon 5 of 8	ENSP00000373355.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251232 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.57
Sift	Benign	0.051	T
Sift4G	Benign	0.085	T
Polyphen		0.24	B
Vest4		0.60
MutPred		0.70		Loss of stability (P = 0.0406)
MVP		0.94
MPC		0.13
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.79
gMVP		0.83
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: 25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137852849; hg19: chr3-4458816;