3-196885683-A-T

Variant names:

• chr3-196885683-A-T
• rs1412617876
• NM_152699.5:c.502A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152699.5(SENP5):​c.502A>T​(p.Met168Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: SENP5 NM_152699.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50

Genes affected

SENP5 (HGNC:28407): (SUMO specific peptidase 5) 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 SENP5, 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14066392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SENP5	NM_152699.5	c.502A>T	p.Met168Leu	missense_variant	Exon 2 of 10	ENST00000323460.10	NP_689912.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SENP5	ENST00000323460.10	c.502A>T	p.Met168Leu	missense_variant	Exon 2 of 10	1	NM_152699.5	ENSP00000327197.5
SENP5	ENST00000445299.6	c.502A>T	p.Met168Leu	missense_variant	Exon 2 of 9	2		ENSP00000390231.2
SENP5	ENST00000419026.5	c.-17-13983A>T		intron_variant	Intron 1 of 8	3		ENSP00000396927.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251006 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.502A>T (p.M168L) alteration is located in exon 2 (coding exon 1) of the SENP5 gene. This alteration results from a A to T substitution at nucleotide position 502, causing the methionine (M) at amino acid position 168 to be replaced by a leucine (L). 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	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.0054	.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.40	T;T
Polyphen		0.085	.;B
Vest4		0.37
MutPred		0.21		Gain of catalytic residue at M168 (P = 0.0281);Gain of catalytic residue at M168 (P = 0.0281);
MVP		0.37
MPC		0.49
ClinPred		0.45	T
GERP RS		4.0
Varity_R		0.35
gMVP		0.21

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: rs1412617876; hg19: chr3-196612554;