Genetic Variant SETMAR:p.Thr8Arg (chr3-4303393-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006515.4(SETMAR):c.23C>G(p.Thr8Arg) 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 benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T8M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SETMAR
NM_006515.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.462

Publications

0 publications found

Variant links:

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]

SETMAR links:

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

SUMF1 links:

ENSG00000286579 (HGNC:):

ENSG00000286579 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05201575).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETMAR	NM_006515.4	MANE Select	c.23C>G	p.Thr8Arg	missense	Exon 1 of 3	NP_006506.3	Q53H47-1
SETMAR	NM_001243723.2		c.23C>G	p.Thr8Arg	missense	Exon 1 of 4	NP_001230652.1	Q53H47-3
SETMAR	NM_001320678.2		c.23C>G	p.Thr8Arg	missense	Exon 1 of 2	NP_001307607.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETMAR	ENST00000358065.5	TSL:1 MANE Select	c.23C>G	p.Thr8Arg	missense	Exon 1 of 3	ENSP00000373354.3	Q53H47-1
SETMAR	ENST00000430981.1	TSL:1	c.23C>G	p.Thr8Arg	missense	Exon 1 of 2	ENSP00000403000.1	Q53H47-2
SETMAR	ENST00000425046.1	TSL:1	n.23C>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000397463.1	F8WB33

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.44

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0050

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.45

M_CAP

Benign

0.041

MetaRNN

Benign

0.052

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

-0.69

PhyloP100

-0.46

PrimateAI

Benign

0.27

PROVEAN

Benign

0.23

REVEL

Benign

0.12

Sift

Benign

0.15

Sift4G

Benign

0.34

Vest4

0.049

MutPred

0.23

Gain of MoRF binding (P = 0.0048)

MVP

0.58

MPC

0.029

ClinPred

0.080

GERP RS

-4.6

PromoterAI

-0.080

Neutral

(source)

Varity_R

0.061

gMVP

0.073

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over