Variant 22-23694963-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_153615.2(RGL4):c.1030G>C(p.Glu344Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,613,346 control chromosomes in the GnomAD database, including 1 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 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

RGL4
NM_153615.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.10

Variant links:

Genes affected

RGL4 (HGNC:31911): (ral guanine nucleotide dissociation stimulator like 4) This oncogene encodes a protein similar to guanine nucleotide exchange factor Ral guanine dissociation stimulator. Increased expression of this gene leads to translocation of the encoded protein to the cell membrane. The encoded protein can activate several pathways, including the Ras-Raf-MEK-ERK cascade. [provided by RefSeq, Jul 2016]

RGL4 links:

GUSBP11 (HGNC:42325): (GUSB pseudogene 11) This transcribed pseudogene is similar to two functional genes. The 5' portion of the pseudogene is related to glucuronidase, beta, and the 3' portion is related to immunoglobulin lambda-like polypeptide 1. [provided by RefSeq, Jul 2011]

GUSBP11 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=0.007566333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RGL4	NM_153615.2 linkuse as main transcript	c.1030G>C	p.Glu344Gln	missense_variant	6/11	ENST00000290691.10	NP_705843.1
GUSBP11	NR_024448.2 linkuse as main transcript	n.1717C>G		non_coding_transcript_exon_variant	8/12
RGL4	NM_001329424.3 linkuse as main transcript	c.1030G>C	p.Glu344Gln	missense_variant	6/12		NP_001316353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGL4	ENST00000290691.10 linkuse as main transcript	c.1030G>C	p.Glu344Gln	missense_variant	6/11	1	NM_153615.2	ENSP00000290691	P2	Q8IZJ4-1
GUSBP11	ENST00000435868.1 linkuse as main transcript	n.711+19248C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251408

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461054

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.00224

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152292

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000820

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000272

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Apr 22, 2022

The c.1030G>C (p.E344Q) alteration is located in exon 6 (coding exon 6) of the RGL4 gene. This alteration results from a G to C substitution at nucleotide position 1030, causing the glutamic acid (E) at amino acid position 344 to be replaced by a glutamine (Q). 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

0.088

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.16

DANN

Benign

0.33

DEOGEN2

Benign

0.020

.;.;.;T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.81

T;T;T;T;T

M_CAP

Benign

0.00096

MetaRNN

Benign

0.0076

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.56

.;.;.;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.17

N;.;.;N;N

REVEL

Benign

0.071

Sift

Benign

0.20

T;.;.;T;T

Sift4G

Benign

0.59

T;T;T;T;T

Polyphen

0.087

.;.;.;B;.

Vest4

0.15

MVP

0.29

MPC

0.082

ClinPred

0.029

GERP RS

-4.6

Varity_R

0.066

gMVP

0.088

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