22-23692990-C-T

Position:

chr22-23692990-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.695C>T(p.Ala232Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000903 in 1,594,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 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 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

RGL4
NM_153615.2 missense, splice_region

Scores

Splicing: ADA: 0.004682

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

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=0.028927594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RGL4	NM_153615.2 linkuse as main transcript	c.695C>T	p.Ala232Val	missense_variant, splice_region_variant	3/11	ENST00000290691.10
GUSBP11	NR_024448.2 linkuse as main transcript	n.2561+1129G>A		intron_variant, non_coding_transcript_variant
RGL4	NM_001329424.3 linkuse as main transcript	c.695C>T	p.Ala232Val	missense_variant, splice_region_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGL4	ENST00000290691.10 linkuse as main transcript	c.695C>T	p.Ala232Val	missense_variant, splice_region_variant	3/11	1	NM_153615.2	P2	Q8IZJ4-1
	ENST00000417194.5 linkuse as main transcript	n.196G>A		non_coding_transcript_exon_variant	1/3	1
GUSBP11	ENST00000435868.1 linkuse as main transcript	n.711+21221G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000154

AC:

AN:

233708

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

126388

show subpopulations

Gnomad AFR exome

AF:

0.00170

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000727

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000384

Gnomad OTH exome

AF:

0.000351

GnomAD4 exome

AF:

0.0000485

AC:

AN:

1442336

Hom.:

Cov.:

AF XY:

0.0000322

AC XY:

AN XY:

714968

show subpopulations

Gnomad4 AFR exome

AF:

0.00141

Gnomad4 AMR exome

AF:

0.0000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000118

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.000486

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000620

Hom.:

Bravo

AF:

0.000480

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

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 02, 2021

The c.695C>T (p.A232V) alteration is located in exon 3 (coding exon 3) of the RGL4 gene. This alteration results from a C to T substitution at nucleotide position 695, causing the alanine (A) at amino acid position 232 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.7

DANN

Benign

0.91

Eigen

Benign

-0.88

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.78

T;T;T;T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.029

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.1

D;.;.;D;D

REVEL

Benign

0.17

Sift

Benign

0.12

T;.;.;T;T

Sift4G

Benign

0.20

T;T;T;T;T

Polyphen

0.54

.;.;.;P;.

Vest4

0.17

MVP

0.38

MPC

0.14

ClinPred

0.091

GERP RS

-5.3

Varity_R

0.082

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0047

dbscSNV1_RF

Benign

0.22

SpliceAI score (max)

0.010

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