Variant 6-75666723-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_015571.4(SENP6):c.1006A>G(p.Ser336Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000731 in 1,367,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

SENP6
NM_015571.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.12

Variant links:

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]

SENP6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity SENP6_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SENP6	NM_015571.4 linkuse as main transcript	c.1006A>G	p.Ser336Gly	missense_variant	10/24	ENST00000447266.7	NP_056386.2	Q9GZR1-1B3KMM0
SENP6	NM_001100409.3 linkuse as main transcript	c.985A>G	p.Ser329Gly	missense_variant	9/23		NP_001093879.1	Q9GZR1-2B3KMM0
SENP6	NM_001304792.2 linkuse as main transcript	c.985A>G	p.Ser329Gly	missense_variant	9/15		NP_001291721.1	Q9GZR1F8W6D9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SENP6	ENST00000447266.7 linkuse as main transcript	c.1006A>G	p.Ser336Gly	missense_variant	10/24	1	NM_015571.4	ENSP00000402527.2	Q9GZR1-1
SENP6	ENST00000370010.6 linkuse as main transcript	c.985A>G	p.Ser329Gly	missense_variant	9/23	1		ENSP00000359027.2	Q9GZR1-2
SENP6	ENST00000327284.12 linkuse as main transcript	c.985A>G	p.Ser329Gly	missense_variant	9/15	2		ENSP00000321820.8	F8W6D9
SENP6	ENST00000424947.6 linkuse as main transcript	c.676A>G	p.Ser226Gly	missense_variant	7/13	2		ENSP00000391426.2	H0Y4F4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.31e-7

AC:

AN:

1367654

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

679058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.50e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2023

The c.1006A>G (p.S336G) alteration is located in exon 10 (coding exon 10) of the SENP6 gene. This alteration results from a A to G substitution at nucleotide position 1006, causing the serine (S) at amino acid position 336 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

Uncertain

0.42

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

.;.;T;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Benign

0.072

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.2

.;.;M;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.8

D;D;D;D

REVEL

Benign

0.27

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.78

MutPred

0.15

.;.;Loss of phosphorylation at S336 (P = 0.0134);.;

MVP

0.21

MPC

0.49

ClinPred

0.97

GERP RS

5.3

Varity_R

0.55

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over