chr3-4313468-A-G

Position:

• chr3-4313468-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000358065.5(SETMAR):​c.727A>G​(p.Lys243Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETMAR ENST00000358065.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETMAR	NM_006515.4	c.727A>G	p.Lys243Glu	missense_variant	2/3	ENST00000358065.5	NP_006506.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETMAR	ENST00000358065.5	c.727A>G	p.Lys243Glu	missense_variant	2/3	1	NM_006515.4	ENSP00000373354	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.727A>G (p.K243E) alteration is located in exon 2 (coding exon 2) of the SETMAR gene. This alteration results from a A to G substitution at nucleotide position 727, causing the lysine (K) at amino acid position 243 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;T
Vest4		0.45
MVP		0.77
MPC		0.13
ClinPred		0.95	D
GERP RS		4.0
Varity_R		0.56
gMVP		0.15

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: chr3-4355152;