rs17414086

chr6-75634715-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015571.4(SENP6):c.362C>T(p.Thr121Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,556,674 control chromosomes in the GnomAD database, including 89,828 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (5903 hom., cov: 32)
  • Exomes 𝑓: 0.33 (83925 hom.)
• Consequence: SENP6 NM_015571.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14

Genes affected

SENP6 (HGNC:20944): (SUMO specific peptidase 6) Ubiquitin-like molecules (UBLs), such as SUMO1 (UBL1; MIM 601912), are structurally related to ubiquitin (MIM 191339) and can be ligated to target proteins in a similar manner as ubiquitin. However, covalent attachment of UBLs does not result in degradation of the modified proteins. SUMO1 modification is implicated in the targeting of RANGAP1 (MIM 602362) to the nuclear pore complex, as well as in stabilization of I-kappa-B-alpha (NFKBIA; MIM 164008) from degradation by the 26S proteasome. Like ubiquitin, UBLs are synthesized as precursor proteins, with 1 or more amino acids following the C-terminal glycine-glycine residues of the mature UBL protein. Thus, the tail sequences of the UBL precursors need to be removed by UBL-specific proteases, such as SENP6, prior to their conjugation to target proteins (Kim et al., 2000 [PubMed 10799485]). SENPs also display isopeptidase activity for deconjugation of SUMO-conjugated substrates (Lima and Reverter, 2008 [PubMed 18799455]).[supplied by OMIM, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005008906).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SENP6	NM_015571.4	c.362C>T	p.Thr121Met	missense_variant	5/24	ENST00000447266.7
SENP6	NM_001100409.3	c.362C>T	p.Thr121Met	missense_variant	5/23
SENP6	NM_001304792.2	c.362C>T	p.Thr121Met	missense_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SENP6	ENST00000447266.7	c.362C>T	p.Thr121Met	missense_variant	5/24	1	NM_015571.4	P2

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37137 AN: 151868 Hom.: 5905 Cov.: 32

Gnomad AFR AF: 0.0650

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.0445

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.248

GnomAD3 exomes AF: 0.270 AC: 57500 AN: 212688 Hom.: 9272 AF XY: 0.281 AC XY: 32762 AN XY: 116528

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.0393

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.334 AC: 468676 AN: 1404688 Hom.: 83925 Cov.: 27 AF XY: 0.333 AC XY: 232541 AN XY: 698704

Gnomad4 AFR exome AF: 0.0535

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.279

Gnomad4 EAS exome AF: 0.0352

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.280

Gnomad4 NFE exome AF: 0.368

Gnomad4 OTH exome AF: 0.302

GnomAD4 genome AF: 0.244 AC: 37118 AN: 151986 Hom.: 5903 Cov.: 32 AF XY: 0.239 AC XY: 17743 AN XY: 74276

Gnomad4 AFR AF: 0.0648

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.0446

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.285

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.245

Alfa AF: 0.323 Hom.: 14148

Bravo AF: 0.228

TwinsUK AF: 0.379 AC: 1405

ALSPAC AF: 0.368 AC: 1420

ESP6500AA AF: 0.0605 AC: 224

ESP6500EA AF: 0.357 AC: 2915

ExAC AF: 0.266 AC: 32091

Asia WGS AF: 0.143 AC: 502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	17
Dann	Benign	0.96
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.69	T;T;T;T;T
MetaRNN	Benign	0.0050	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;L;.;.
MutationTaster	Benign	0.99	P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.83	N;N;N;D;N
REVEL	Benign	0.12
Sift	Benign	0.057	T;T;T;T;T
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.96	D;D;P;.;.
Vest4		0.15
MPC		0.23
ClinPred		0.012	T
GERP RS		3.7
Varity_R		0.020
gMVP		0.19

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: rs17414086; hg19: chr6-76344431;