rs137917233

Variant names:

• chr3-4418071-C-G
• rs137917233
• NM_182760.4:c.664G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_182760.4(SUMF1):​c.664G>C​(p.Gly222Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,614,078 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (3 hom.)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 2.16
• 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: Benign. The variant received -11 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, 6 uncertain in NM_182760.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.028752208).
• BP6: Variant 3-4418071-C-G is Benign according to our data. Variant chr3-4418071-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 345316.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00173 (264/152302) while in subpopulation AMR AF = 0.00601 (92/15302). AF 95% confidence interval is 0.00502. There are 0 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.664G>C	p.Gly222Arg	missense	Exon 5 of 9	NP_877437.2
	SUMF1	NM_001164675.2		c.664G>C	p.Gly222Arg	missense	Exon 5 of 8	NP_001158147.1	Q8NBK3-5
	SUMF1	NM_001164674.2		c.589G>C	p.Gly197Arg	missense	Exon 4 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.664G>C	p.Gly222Arg	missense	Exon 5 of 9	ENSP00000272902.5	Q8NBK3-1
	SUMF1	ENST00000405420.2	TSL:1	c.664G>C	p.Gly222Arg	missense	Exon 5 of 8	ENSP00000384977.2	Q8NBK3-5
	SUMF1	ENST00000948922.1		c.685G>C	p.Gly229Arg	missense	Exon 5 of 9	ENSP00000618981.1

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 264 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00163 AC: 409 AN: 251404 AF XY: 0.00155

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00234 AC: 3421 AN: 1461776 Hom.: 3 Cov.: 31 AF XY: 0.00223 AC XY: 1624 AN XY: 727188

African (AFR) AF: 0.000299 AC: 10 AN: 33474

American (AMR) AF: 0.00233 AC: 104 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86250

European-Finnish (FIN) AF: 0.000824 AC: 44 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00279 AC: 3108 AN: 1112006

Other (OTH) AF: 0.00187 AC: 113 AN: 60384

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.00176 AC XY: 131 AN XY: 74484

African (AFR) AF: 0.000361 AC: 15 AN: 41568

American (AMR) AF: 0.00601 AC: 92 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 68016

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00211 Hom.: 0

Bravo AF: 0.00194

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00159 AC: 193

EpiCase AF: 0.00278

EpiControl AF: 0.00255

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	Multiple sulfatase deficiency (6)
-	3	2	not provided (5)
-	-	1	SUMF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.029	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		2.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.98	D
Vest4		0.54
MutPred		0.80		Loss of catalytic residue at A221 (P = 0.0391)
MVP		0.93
MPC		0.17
ClinPred		0.080	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.50
gMVP		0.83
Mutation Taster		=72/28	polymorphism

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: rs137917233; hg19: chr3-4459755; COSMIC: COSV105071735; COSMIC: COSV105071735;