17-7563632-T-C

Variant names:

• chr17-7563632-T-C
• NM_015670.6:c.556T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015670.6(SENP3):​c.556T>C​(p.Phe186Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 6.9e-7 (0 hom.)
• Consequence: SENP3 NM_015670.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59
• Publications: 0 publications found

Genes affected

SENP3 (HGNC:17862): (SUMO specific peptidase 3) The reversible posttranslational modification of proteins by the addition of small ubiquitin-like SUMO proteins (see SUMO1; MIM 601912) is required for numerous biologic processes. SUMO-specific proteases, such as SENP3, are responsible for the initial processing of SUMO precursors to generate a C-terminal diglycine motif required for the conjugation reaction. They also have isopeptidase activity for the removal of SUMO from high molecular mass SUMO conjugates (Di Bacco et al., 2006 [PubMed 16738315]).[supplied by OMIM, Jun 2009]

SENP3-EIF4A1 (HGNC:49182): (SENP3-EIF4A1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring SUMO1/sentrin/SMT3 specific peptidase 3 (SENP3) and eukaryotic translation initiation factor 4A1 (EIF4A1) genes on chromosome 17. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

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=0.049126297).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015670.6. 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
	SENP3	NM_015670.6	MANE Select	c.556T>C	p.Phe186Leu	missense	Exon 2 of 11	NP_056485.2
	SENP3-EIF4A1	NR_037926.1		n.839T>C		non_coding_transcript_exon	Exon 2 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SENP3	ENST00000321337.12	TSL:1 MANE Select	c.556T>C	p.Phe186Leu	missense	Exon 2 of 11	ENSP00000314029.8	Q9H4L4
	SENP3-EIF4A1	ENST00000614237.1	TSL:2	n.346T>C		non_coding_transcript_exon	Exon 1 of 21	ENSP00000483614.1	A0A087X0R7
	SENP3	ENST00000937871.1		c.556T>C	p.Phe186Leu	missense	Exon 1 of 10	ENSP00000607930.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451896 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 721966

African (AFR) AF: 0.00 AC: 0 AN: 33182

American (AMR) AF: 0.00 AC: 0 AN: 42868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.00 AC: 0 AN: 84928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107992

Other (OTH) AF: 0.00 AC: 0 AN: 59918

GnomAD4 genome Cov.: 32

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	Uncertain	0.53
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.060
Sift	Benign	0.46	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.095		Gain of glycosylation at S181 (P = 0.0976)
MVP		0.25
MPC		0.31
ClinPred		0.20	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.25
Mutation Taster		=95/5	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

hg19: chr17-7466949;