17-7563614-C-T

Variant names:

• chr17-7563614-C-T
• rs752455114
• NM_015670.6:c.538C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015670.6(SENP3):​c.538C>T​(p.Pro180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,594,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SENP3 NM_015670.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025538504).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SENP3	NM_015670.6	c.538C>T	p.Pro180Ser	missense_variant	Exon 2 of 11	ENST00000321337.12	NP_056485.2
SENP3-EIF4A1	NR_037926.1	n.821C>T		non_coding_transcript_exon_variant	Exon 2 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SENP3	ENST00000321337.12	c.538C>T	p.Pro180Ser	missense_variant	Exon 2 of 11	1	NM_015670.6	ENSP00000314029.8
SENP3-EIF4A1	ENST00000614237.1	n.328C>T		non_coding_transcript_exon_variant	Exon 1 of 21	2		ENSP00000483614.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000932 AC: 20 AN: 214518 Hom.: 0 AF XY: 0.0000766 AC XY: 9 AN XY: 117428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000189

GnomAD4 exome AF: 0.0000132 AC: 19 AN: 1441986 Hom.: 0 Cov.: 47 AF XY: 0.0000126 AC XY: 9 AN XY: 716112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000333

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.0000504

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000415 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.538C>T (p.P180S) alteration is located in exon 2 (coding exon 1) of the SENP3 gene. This alteration results from a C to T substitution at nucleotide position 538, causing the proline (P) at amino acid position 180 to be replaced by a serine (S). 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	0.068
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.13
Sift	Benign	0.056	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.074	B;B
Vest4		0.25
MutPred		0.092		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.38
MPC		0.27
ClinPred		0.062	T
GERP RS		4.5
Varity_R		0.10
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs752455114; hg19: chr17-7466931;