17-7563377-A-G

Variant names:

• chr17-7563377-A-G
• rs569520715
• NM_015670.6:c.301A>G

Variant summary

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

The NM_015670.6(SENP3):​c.301A>G​(p.Arg101Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000728 in 1,551,320 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: SENP3 NM_015670.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

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=0.027621001).
• BS2: High AC in GnomAd4 at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SENP3	NM_015670.6	c.301A>G	p.Arg101Gly	missense_variant	Exon 2 of 11	ENST00000321337.12	NP_056485.2
SENP3-EIF4A1	NR_037926.1	n.584A>G		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.301A>G	p.Arg101Gly	missense_variant	Exon 2 of 11	1	NM_015670.6	ENSP00000314029.8
SENP3-EIF4A1	ENST00000614237.1	n.91A>G		non_coding_transcript_exon_variant	Exon 1 of 21	2		ENSP00000483614.1

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000824

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000327 AC: 51 AN: 156132 Hom.: 0 AF XY: 0.000302 AC XY: 25 AN XY: 82828

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.0000810

Gnomad ASJ exome AF: 0.000471

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000757 AC: 1059 AN: 1399022 Hom.: 1 Cov.: 31 AF XY: 0.000736 AC XY: 508 AN XY: 690036

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000205

Gnomad4 NFE exome AF: 0.000931

Gnomad4 OTH exome AF: 0.000638

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74464

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000824

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.000134 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.301A>G (p.R101G) alteration is located in exon 2 (coding exon 1) of the SENP3 gene. This alteration results from a A to G substitution at nucleotide position 301, causing the arginine (R) at amino acid position 101 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	0.084
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.075
Sift	Benign	0.20	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0	B;B
Vest4		0.21
MVP		0.21
MPC		0.34
ClinPred		0.013	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs569520715; hg19: chr17-7466694;