chr3-4467245-T-C

Variant names:

• chr3-4467245-T-C
• rs137852855
• NM_182760.4:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_182760.4(SUMF1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SUMF1 NM_182760.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.04
• Publications: 4 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

LOC124909340 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 26 pathogenic variants. Next in-frame start position is after 91 codons. Genomic position: 4453049. Lost 0.241 part of the original CDS.
• PS1: Another start lost variant in NM_182760.4 (SUMF1) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-4467245-T-C is Pathogenic according to our data. Variant chr3-4467245-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2679.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMF1	NM_182760.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 9	NP_877437.2
	SUMF1	NM_001164675.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 8	NP_001158147.1	Q8NBK3-5
	SUMF1	NM_001164674.2		c.1A>G	p.Met1?	start_lost	Exon 1 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.1A>G	p.Met1?	start_lost	Exon 1 of 9	ENSP00000272902.5	Q8NBK3-1
	SUMF1	ENST00000405420.2	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 8	ENSP00000384977.2	Q8NBK3-5
	SUMF1	ENST00000948922.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 9	ENSP00000618981.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455566 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 723586

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 84912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109612

Other (OTH) AF: 0.00 AC: 0 AN: 60072

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Multiple sulfatase deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
PhyloP100		3.0
PROVEAN	Benign	-0.88	N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.71	P
Vest4		0.93
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0836)
MVP		0.94
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.91	Under-expression
Varity_R		0.93
gMVP		0.65
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852855; hg19: chr3-4508929;