Variant 16-1777141-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000566339.6(SPSB3):c.1024C>G(p.Arg342Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,611,612 control chromosomes in the GnomAD database, including 6 homozygotes. 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 (★).

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

SPSB3
ENST00000566339.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.58

Variant links:

Genes affected

SPSB3 (HGNC:30629): (splA/ryanodine receptor domain and SOCS box containing 3) Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be located in cytosol. Predicted to be part of SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

SPSB3 links:

EME2 (HGNC:27289): (essential meiotic structure-specific endonuclease subunit 2) EME2 forms a heterodimer with MUS81 (MIM 606591) that functions as an XPF (MIM 278760)-type flap/fork endonuclease in DNA repair (Ciccia et al., 2007 [PubMed 17289582]).[supplied by OMIM, Mar 2008]

EME2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021599412).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPSB3	NM_080861.4 linkuse as main transcript	c.1024C>G	p.Arg342Gly	missense_variant	7/7	ENST00000566339.6	NP_543137.2
EME2	NM_001257370.2 linkuse as main transcript	c.*903G>C		3_prime_UTR_variant	8/8	ENST00000568449.7	NP_001244299.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPSB3	ENST00000566339.6 linkuse as main transcript	c.1024C>G	p.Arg342Gly	missense_variant	7/7	1	NM_080861.4	ENSP00000457206	P1
EME2	ENST00000568449.7 linkuse as main transcript	c.*903G>C		3_prime_UTR_variant	8/8	1	NM_001257370.2	ENSP00000457353	P1	A4GXA9-1

Frequencies

GnomAD3 genomes

AF:

0.000815

AC:

124

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000646

AC:

159

AN:

246110

Hom.:

AF XY:

0.000604

AC XY:

AN XY:

134210

show subpopulations

Gnomad AFR exome

AF:

0.000321

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000548

Gnomad SAS exome

AF:

0.000426

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.000829

GnomAD4 exome

AF:

0.00133

AC:

1942

AN:

1459276

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

940

AN XY:

726010

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000510

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00161

Gnomad4 OTH exome

AF:

0.00114

GnomAD4 genome

AF:

0.000814

AC:

124

AN:

152336

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00157

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000875

Hom.:

Bravo

AF:

0.000922

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000817

AC:

ExAC

AF:

0.000545

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.00148

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

Aug 13, 2021

The c.1024C>G (p.R342G) alteration is located in exon 7 (coding exon 6) of the SPSB3 gene. This alteration results from a C to G substitution at nucleotide position 1024, causing the arginine (R) at amino acid position 342 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

Benign

0.070

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.013

T;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.37

.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

0.13

N;N

REVEL

Benign

0.053

Sift

Benign

0.27

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.0030

B;B

Vest4

0.084

MVP

0.082

MPC

0.40

ClinPred

0.014

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.29

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

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