SETMAR p.Gly74Arg

Variant names:

• chr3-4312961-G-C
• NM_006515.4:c.220G>C
• SETMAR p.Gly74Arg

Your query was ambiguous. Multiple possible variants found:

• chr3-4312961-G-C
• chr3-4312961-G-A
• chr3-4312961-GGA-CGT
• chr3-4312961-GGA-CGC
• chr3-4312961-GGA-CGG
• chr3-4312961-GGA-AGG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006515.4(SETMAR):​c.220G>C​(p.Gly74Arg) variant causes a missense change involving the alteration of a 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETMAR NM_006515.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.99
• Publications: 0 publications found

Genes affected

SETMAR (HGNC:10762): (SET domain and mariner transposase fusion gene) This gene encodes a fusion protein that contains an N-terminal histone-lysine N-methyltransferase domain and a C-terminal mariner transposase domain. The encoded protein binds DNA and functions in DNA repair activities including non-homologous end joining and double strand break repair. The SET domain portion of this protein specifically methylates histone H3 lysines 4 and 36. This gene exists as a fusion gene only in anthropoid primates, other organisms lack mariner transposase domain. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

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: ClinGen, Orphanet, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006515.4. 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
	SETMAR	NM_006515.4	MANE Select	c.220G>C	p.Gly74Arg	missense	Exon 2 of 3	NP_006506.3	Q53H47-1
	SETMAR	NM_001243723.2		c.220G>C	p.Gly74Arg	missense	Exon 2 of 4	NP_001230652.1	Q53H47-3
	SETMAR	NM_001276325.2		c.220G>C	p.Gly74Arg	missense	Exon 2 of 2	NP_001263254.1	Q53H47-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETMAR	ENST00000358065.5	TSL:1 MANE Select	c.220G>C	p.Gly74Arg	missense	Exon 2 of 3	ENSP00000373354.3	Q53H47-1
	SETMAR	ENST00000430981.1	TSL:1	c.220G>C	p.Gly74Arg	missense	Exon 2 of 2	ENSP00000403000.1	Q53H47-2
	SETMAR	ENST00000425046.1	TSL:1	n.157-686G>C		intron	N/A	ENSP00000397463.1	F8WB33

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.075	T
Varity_R		0.83
gMVP		0.42
Mutation Taster		=51/49	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-4354645;