rs34451237

Positions:

• chr6-75621592-A-G

Variant summary

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

The NM_015571.4(SENP6):​c.113A>G​(p.His38Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00169 in 1,610,814 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: SENP6 NM_015571.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027658641).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SENP6	NM_015571.4	c.113A>G	p.His38Arg	missense_variant	2/24	ENST00000447266.7	NP_056386.2
SENP6	NM_001100409.3	c.113A>G	p.His38Arg	missense_variant	2/23		NP_001093879.1
SENP6	NM_001304792.2	c.113A>G	p.His38Arg	missense_variant	2/15		NP_001291721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SENP6	ENST00000447266.7	c.113A>G	p.His38Arg	missense_variant	2/24	1	NM_015571.4	ENSP00000402527.2

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000944 AC: 235 AN: 248916 Hom.: 0 AF XY: 0.000896 AC XY: 121 AN XY: 135070

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00175 AC: 2558 AN: 1458600 Hom.: 4 Cov.: 28 AF XY: 0.00170 AC XY: 1234 AN XY: 725882

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.000575

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000955

Gnomad4 NFE exome AF: 0.00218

Gnomad4 OTH exome AF: 0.000863

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.000982 AC XY: 73 AN XY: 74372

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00103

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000280 AC: 1

ESP6500EA AF: 0.00148 AC: 12

ExAC AF: 0.000952 AC: 115

EpiCase AF: 0.00169

EpiControl AF: 0.00231

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0040	.;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.091
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.76	P;P;P
Vest4		0.59
MVP		0.23
MPC		0.36
ClinPred		0.045	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.052

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: rs34451237; hg19: chr6-76331308; COSMIC: COSV99046326;