3-4376365-G-C

Variant names:

• chr3-4376365-G-C
• rs137852845
• NM_182760.4:c.979C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_182760.4(SUMF1):​c.979C>G​(p.Arg327Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a disulfide_bond (size 147) in uniprot entity SUMF1_HUMAN there are 28 pathogenic changes around while only 3 benign (90%) in NM_182760.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUMF1	NM_182760.4	c.979C>G	p.Arg327Gly	missense_variant	Exon 8 of 9	ENST00000272902.10	NP_877437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUMF1	ENST00000272902.10	c.979C>G	p.Arg327Gly	missense_variant	Exon 8 of 9	1	NM_182760.4	ENSP00000272902.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.
PhyloP100		2.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.85
MutPred		0.68		Loss of MoRF binding (P = 0.0261);.;.;
MVP		0.89
MPC		0.52
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.92
Mutation Taster		=41/59	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

Publications

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Other links and lift over

dbSNP: rs137852845; hg19: chr3-4418049;