6-75602535-G-C

Position:

• chr6-75602535-G-C

Variant summary

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

The NM_015571.4(SENP6):​c.11G>C​(p.Gly4Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SENP6 NM_015571.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.02

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 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=0.22343203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SENP6	NM_015571.4	c.11G>C	p.Gly4Ala	missense_variant	1/24	ENST00000447266.7	NP_056386.2
SENP6	NM_001100409.3	c.11G>C	p.Gly4Ala	missense_variant	1/23		NP_001093879.1
SENP6	NM_001304792.2	c.11G>C	p.Gly4Ala	missense_variant	1/15		NP_001291721.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SENP6	ENST00000447266.7	c.11G>C	p.Gly4Ala	missense_variant	1/24	1	NM_015571.4	ENSP00000402527.2
SENP6	ENST00000370010.6	c.11G>C	p.Gly4Ala	missense_variant	1/23	1		ENSP00000359027.2
SENP6	ENST00000327284.12	c.11G>C	p.Gly4Ala	missense_variant	1/15	2		ENSP00000321820.8
SENP6	ENST00000493959.6	n.11G>C		non_coding_transcript_exon_variant	1/6	3		ENSP00000425624.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.11G>C (p.G4A) alteration is located in exon 1 (coding exon 1) of the SENP6 gene. This alteration results from a G to C substitution at nucleotide position 11, causing the glycine (G) at amino acid position 4 to be replaced by an alanine (A). 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	0.24
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.81
DEOGEN2	Benign	0.0041	.;.;T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.82	T;T;T
Polyphen		0.97	D;P;P
Vest4		0.34
MutPred		0.19		Loss of catalytic residue at A3 (P = 0.0636);Loss of catalytic residue at A3 (P = 0.0636);Loss of catalytic residue at A3 (P = 0.0636);
MVP		0.29
MPC		0.53
ClinPred		0.83	D
GERP RS		3.1
Varity_R		0.36
gMVP		0.041

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-76312251;