chr3-4303413-G-A

Variant names:

• chr3-4303413-G-A
• rs756322943
• NM_006515.4:c.43G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006515.4(SETMAR):​c.43G>A​(p.Ala15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000925 in 1,405,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000093 (0 hom.)
• Consequence: SETMAR NM_006515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.951
• 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: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ENSG00000286579 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25508982).

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.43G>A	p.Ala15Thr	missense	Exon 1 of 3	NP_006506.3	Q53H47-1
	SETMAR	NM_001243723.2		c.43G>A	p.Ala15Thr	missense	Exon 1 of 4	NP_001230652.1	Q53H47-3
	SETMAR	NM_001320678.2		c.43G>A	p.Ala15Thr	missense	Exon 1 of 2	NP_001307607.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETMAR	ENST00000358065.5	TSL:1 MANE Select	c.43G>A	p.Ala15Thr	missense	Exon 1 of 3	ENSP00000373354.3	Q53H47-1
	SETMAR	ENST00000430981.1	TSL:1	c.43G>A	p.Ala15Thr	missense	Exon 1 of 2	ENSP00000403000.1	Q53H47-2
	SETMAR	ENST00000425046.1	TSL:1	n.43G>A		non_coding_transcript_exon	Exon 1 of 3	ENSP00000397463.1	F8WB33

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000154 AC: 3 AN: 195364 AF XY: 0.00000930

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000925 AC: 13 AN: 1405098 Hom.: 0 Cov.: 31 AF XY: 0.00000860 AC XY: 6 AN XY: 697616

African (AFR) AF: 0.0000344 AC: 1 AN: 29042

American (AMR) AF: 0.000141 AC: 5 AN: 35470

Ashkenazi Jewish (ASJ) AF: 0.0000403 AC: 1 AN: 24828

East Asian (EAS) AF: 0.00 AC: 0 AN: 33012

South Asian (SAS) AF: 0.00 AC: 0 AN: 77978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1088414

Other (OTH) AF: 0.0000345 AC: 2 AN: 57990

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T
Eigen	Benign	0.025
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.95
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.29
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.085	T
Vest4		0.24
MVP		0.98
MPC		0.19
ClinPred		0.85	D
GERP RS		5.1
PromoterAI		-0.33	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.092
Mutation Taster		=91/9	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

Other links and lift over

dbSNP: rs756322943; hg19: chr3-4345097;