rs17414086

Variant names:

• chr6-75634715-C-T
• rs17414086
• NM_015571.4:c.362C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 27 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SENP6	NM_015571.4	c.362C>T	p.Thr121Met	missense_variant	Exon 5 of 24	ENST00000447266.7	NP_056386.2
SENP6	NM_001100409.3	c.362C>T	p.Thr121Met	missense_variant	Exon 5 of 23		NP_001093879.1
SENP6	NM_001304792.2	c.362C>T	p.Thr121Met	missense_variant	Exon 5 of 15		NP_001291721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SENP6	ENST00000447266.7	c.362C>T	p.Thr121Met	missense_variant	Exon 5 of 24	1	NM_015571.4	ENSP00000402527.2

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

GnomAD2 exomes AF: 0.270 AC: 57500 AN: 212688 AF XY: 0.281

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 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

African (AFR) AF: 0.0535 AC: 1642 AN: 30692

American (AMR) AF: 0.165 AC: 5060 AN: 30578

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 6818 AN: 24470

East Asian (EAS) AF: 0.0352 AC: 1350 AN: 38356

South Asian (SAS) AF: 0.259 AC: 20068 AN: 77460

European-Finnish (FIN) AF: 0.280 AC: 14841 AN: 52944

Middle Eastern (MID) AF: 0.347 AC: 1946 AN: 5600

European-Non Finnish (NFE) AF: 0.368 AC: 399388 AN: 1086352

Other (OTH) AF: 0.302 AC: 17563 AN: 58236

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

African (AFR) AF: 0.0648 AC: 2689 AN: 41490

American (AMR) AF: 0.213 AC: 3252 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 985 AN: 3472

East Asian (EAS) AF: 0.0446 AC: 231 AN: 5176

South Asian (SAS) AF: 0.252 AC: 1217 AN: 4824

European-Finnish (FIN) AF: 0.285 AC: 2992 AN: 10514

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.366 AC: 24841 AN: 67932

Other (OTH) AF: 0.245 AC: 516 AN: 2104

Alfa AF: 0.307 Hom.: 17996

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
DEOGEN2	Benign	0.0051	.;.;T;.;T
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;.;.
PhyloP100		1.1
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
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17414086; hg19: chr6-76344431; COSMIC: COSV107379649;