22-23692208-C-T

Position:

chr22-23692208-C-T

Variant summary

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

The NM_153615.2(RGL4):c.178C>T(p.Arg60Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RGL4
NM_153615.2 missense, splice_region

Scores

Splicing: ADA: 0.0003913

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -5.10

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:

(HGNC:):

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:

Genome browser will be placed here

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=0.028741896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RGL4	NM_153615.2 linkuse as main transcript	c.178C>T	p.Arg60Cys	missense_variant, splice_region_variant	1/11	ENST00000290691.10
GUSBP11	NR_024448.2 linkuse as main transcript	n.2562-1852G>A		intron_variant, non_coding_transcript_variant
RGL4	NM_001329424.3 linkuse as main transcript	c.178C>T	p.Arg60Cys	missense_variant, splice_region_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGL4	ENST00000290691.10 linkuse as main transcript	c.178C>T	p.Arg60Cys	missense_variant, splice_region_variant	1/11	1	NM_153615.2	P2	Q8IZJ4-1
	ENST00000417194.5 linkuse as main transcript	n.978G>A		non_coding_transcript_exon_variant	1/3	1
GUSBP11	ENST00000435868.1 linkuse as main transcript	n.711+22003G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

248820

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134544

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1460220

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000824

AC:

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

Nov 14, 2023

The c.178C>T (p.R60C) alteration is located in exon 1 (coding exon 1) of the RGL4 gene. This alteration results from a C to T substitution at nucleotide position 178, causing the arginine (R) at amino acid position 60 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

0.098

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.8

DANN

Benign

0.53

DEOGEN2

Benign

0.012

T;.

Eigen

Benign

-2.7

Eigen_PC

Benign

-2.8

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.00083

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.34

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.047

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.085

T;T

Polyphen

0.0

B;.

Vest4

0.025

MutPred

0.50

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.27

MPC

0.10

ClinPred

0.034

GERP RS

-2.4

Varity_R

0.073

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00039

dbscSNV1_RF

Benign

0.23

SpliceAI score (max)

0.15

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