Genetic Variant SENP7:p.Arg904Cys (chr3-101330375-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020654.5(SENP7):c.2710C>T(p.Arg904Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,604,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R904H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

SENP7
NM_020654.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

Variant links:

Genes affected

SENP7 (HGNC:30402): (SUMO specific peptidase 7) The reversible posttranslational modification of proteins by the addition of small ubiquitin-like SUMO proteins (see SUMO1; MIM 601912) is required for many cellular processes. SUMO-specific proteases, such as SENP7, process SUMO precursors to generate a C-terminal diglycine motif required for the conjugation reaction. They also display isopeptidase activity for deconjugation of SUMO-conjugated substrates (Lima and Reverter, 2008 [PubMed 18799455]).[supplied by OMIM, Jun 2009]

SENP7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034907907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SENP7	NM_020654.5 link	c.2710C>T	p.Arg904Cys	missense_variant	Exon 20 of 24	ENST00000394095.7	NP_065705.3	Q9BQF6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SENP7	ENST00000394095.7 link	c.2710C>T	p.Arg904Cys	missense_variant	Exon 20 of 24	1	NM_020654.5	ENSP00000377655.2		Q9BQF6-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000881

AC:

AN:

249722

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

135000

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000441

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000273

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000358

AC:

AN:

1452664

Hom.:

Cov.:

AF XY:

0.0000346

AC XY:

AN XY:

723236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.000315

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000235

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2710C>T (p.R904C) alteration is located in exon 20 (coding exon 20) of the SENP7 gene. This alteration results from a C to T substitution at nucleotide position 2710, causing the arginine (R) at amino acid position 904 to be replaced by a cysteine (C). 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

0.067

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.0040

T;.;T;.;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.81

T;T;T;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.035

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.52

N;.;.;.;.;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.90

N;N;N;N;N;N

REVEL

Benign

0.054

Sift

Benign

0.052

T;D;D;D;D;D

Sift4G

Benign

0.16

T;T;T;T;T;T

Polyphen

1.0

D;B;.;B;B;B

Vest4

0.24

MVP

0.13

MPC

1.1

ClinPred

0.067

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.072

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over