6-75621576-A-T

Variant summary

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

The NM_015571.4(SENP6):c.97A>T(p.Asn33Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SENP6 NM_015571.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SENP6	NM_015571.4	c.97A>T	p.Asn33Tyr	missense_variant	2/24	ENST00000447266.7
SENP6	NM_001100409.3	c.97A>T	p.Asn33Tyr	missense_variant	2/23
SENP6	NM_001304792.2	c.97A>T	p.Asn33Tyr	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SENP6	ENST00000447266.7	c.97A>T	p.Asn33Tyr	missense_variant	2/24	1	NM_015571.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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

Oct 03, 2023

The c.97A>T (p.N33Y) alteration is located in exon 2 (coding exon 2) of the SENP6 gene. This alteration results from a A to T substitution at nucleotide position 97, causing the asparagine (N) at amino acid position 33 to be replaced by a tyrosine (Y). 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	0.20
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.3	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.85
MutPred		0.26		Gain of phosphorylation at N33 (P = 0.0652);Gain of phosphorylation at N33 (P = 0.0652);Gain of phosphorylation at N33 (P = 0.0652);
MVP		0.36
MPC		0.50
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.14

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: rs1768271678; hg19: chr6-76331292;