3-4303494-T-G

Position:

• chr3-4303494-T-G

Variant summary

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

The NM_006515.4(SETMAR):​c.124T>G​(p.Trp42Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000451 in 1,329,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: SETMAR NM_006515.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

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]

(HGNC:):

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	UniProt
SETMAR	NM_006515.4	c.124T>G	p.Trp42Gly	missense_variant	1/3	ENST00000358065.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETMAR	ENST00000358065.5	c.124T>G	p.Trp42Gly	missense_variant	1/3	1	NM_006515.4	P1
	ENST00000653118.1	n.66+7936A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000451 AC: 6 AN: 1329138 Hom.: 0 Cov.: 31 AF XY: 0.00000305 AC XY: 2 AN XY: 655606

Gnomad4 AFR exome AF: 0.0000754

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000205

Gnomad4 NFE exome AF: 0.00000285

Gnomad4 OTH exome AF: 0.00

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

Sep 10, 2021

The c.124T>G (p.W42G) alteration is located in exon 1 (coding exon 1) of the SETMAR gene. This alteration results from a T to G substitution at nucleotide position 124, causing the tryptophan (W) at amino acid position 42 to be replaced by a glycine (G). 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	Benign	0.31
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-0.023
Eigen_PC	Benign	0.019
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.16	T;T;D
Sift4G	Benign	0.87	T;T;T
Vest4		0.42
MVP		0.95
MPC		0.047
ClinPred		0.65	D
GERP RS		5.1
Varity_R		0.69
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: chr3-4345178;