3-4362227-C-A

Variant names:

• chr3-4362227-C-A
• NM_182760.4:c.1042G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_182760.4(SUMF1):​c.1042G>T​(p.Ala348Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUMF1 NM_182760.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.32

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 147) in uniprot entity SUMF1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_182760.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-4362227-C-A is Pathogenic according to our data. Variant chr3-4362227-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3335973.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUMF1	NM_182760.4	c.1042G>T	p.Ala348Ser	missense_variant	Exon 9 of 9	ENST00000272902.10	NP_877437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUMF1	ENST00000272902.10	c.1042G>T	p.Ala348Ser	missense_variant	Exon 9 of 9	1	NM_182760.4	ENSP00000272902.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple sulfatase deficiency Pathogenic:1

May 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SUMF1 c.1042G>T (p.Ala348Ser) results in a conservative amino acid change located in the Sulfatase-modifying factor enzyme (SUMF) domain (IPR005532) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248980 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1042G>T in individuals affected with Multiple Sulfatase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. However, different missense changes affecting the same amino acid (A348P/V) have been reported in affected individuals (HGMD) and been demonstrated to result in severely impaired sulfatase-enhancing activity in in vitro functional studies (PMIDs 32048457, 12757706), indicating that this residue is critical for protein function. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.021	D;D;T;D
Sift4G	Uncertain	0.019	D;T;D;D
Polyphen		0.98	D;.;D;.
Vest4		0.61
MutPred		0.56		Gain of phosphorylation at A348 (P = 0.0187);.;.;.;
MVP		0.88
MPC		0.44
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.50
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-4403911;