3-101326008-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_020654.5(SENP7):c.3088C>T(p.Arg1030Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SENP7
NM_020654.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.20

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.871

PP5

Variant 3-101326008-G-A is Pathogenic according to our data. Variant chr3-101326008-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3340479.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SENP7	NM_020654.5 link	c.3088C>T	p.Arg1030Trp	missense_variant	Exon 24 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.3088C>T	p.Arg1030Trp	missense_variant	Exon 24 of 24	1	NM_020654.5	ENSP00000377655.2		Q9BQF6-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458648

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725596

African (AFR)

AF:

0.00

AC:

AN:

33262

American (AMR)

AF:

0.00

AC:

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.00

AC:

AN:

85958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110274

Other (OTH)

AF:

0.00

AC:

AN:

60200

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151934

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41384

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Arthrogryposis Multiplex Congenita and Immunodeficiency

Pathogenic:1

Aug 01, 2025

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Biallelic loss-of-function variations in the SENP7 gene have been reported in literature to cause fatal arthrogryposis multiplex congenita, early respiratory failure and neutropenia [PMID:37460201]. The c.3088C>T was observed in a fetal sample with symptoms of arthrogryposis. This variant is not present in publicly available population databases like 1000 Genomes, EVS, ExAC, gnomAD, Indian Exome Database or our in-house exome database. This variant has neither been published in literature with SENP7-related conditions nor reported to the clinical databases like ClinVar, Human Genome Mutation Database (HGMD) or OMIM, in any affected individuals. In-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2021, CADD etc predicted this variant to be likely deleterious, however these predictions were not confirmed by published functional studies. Our internal in-silico analysis suggest a deleterious effect of this variant on protein structure and function, however further experimental evidence is required to prove this. By considering PM2 (moderate), PP3 (moderate), PM1 (supporting) and PP4 (supporting) criteria of the ACMG guidelines, we classified this variant as likely pathogenic [Pal et al. Clinical Genetics, 2025]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;.;D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.7

H;.;.;.;.;.

PhyloP100

2.2

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.1

D;D;D;D;D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;D;.;D;D;D

Vest4

0.83

MutPred

0.68

Loss of disorder (P = 0.0126);.;.;.;.;.;

MVP

0.52

MPC

2.0

ClinPred

1.0

GERP RS

3.5

Varity_R

0.93

gMVP

0.97

Mutation Taster

=26/74

disease causing

(source)

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

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3-101326008-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over