Variant 22-23692986-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_153615.2(RGL4):c.691G>C(p.Asp231His) variant causes a missense change. The variant allele was found at a frequency of 0.0000688 in 1,598,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

RGL4
NM_153615.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.65

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:

ENSG00000291299 (HGNC:):

ENSG00000291299 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGL4	NM_153615.2 linkuse as main transcript	c.691G>C	p.Asp231His	missense_variant	3/11	ENST00000290691.10	NP_705843.1	Q8IZJ4-1
RGL4	NM_001329424.3 linkuse as main transcript	c.691G>C	p.Asp231His	missense_variant	3/12		NP_001316353.1	Q8IZJ4Q3ZCN2
GUSBP11	NR_024448.2 linkuse as main transcript	n.2561+1133C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGL4	ENST00000290691.10 linkuse as main transcript	c.691G>C	p.Asp231His	missense_variant	3/11	1	NM_153615.2	ENSP00000290691.5		Q8IZJ4-1
RGL4	ENST00000441897.5 linkuse as main transcript	n.691G>C		non_coding_transcript_exon_variant	5/14	2		ENSP00000396252.1		E9PH21

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152244

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000546

AC:

AN:

237890

Hom.:

AF XY:

0.0000699

AC XY:

AN XY:

128772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000113

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000691

AC:

100

AN:

1446662

Hom.:

Cov.:

AF XY:

0.0000697

AC XY:

AN XY:

717662

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000398

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000852

Gnomad4 OTH exome

AF:

0.0000837

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000785

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

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

Dec 03, 2024

The c.691G>C (p.D231H) alteration is located in exon 3 (coding exon 3) of the RGL4 gene. This alteration results from a G to C substitution at nucleotide position 691, causing the aspartic acid (D) at amino acid position 231 to be replaced by a histidine (H). 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

Pathogenic

0.68

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

.;.;.;T;.

Eigen

Benign

0.14

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.0042

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Benign

-0.77

MutationAssessor

Pathogenic

3.0

.;.;.;M;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.3

D;.;.;D;D

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;.;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

.;.;.;D;.

Vest4

0.43

MutPred

0.86

.;.;.;Gain of ubiquitination at K236 (P = 0.1115);Gain of ubiquitination at K236 (P = 0.1115);

MVP

0.65

MPC

0.47

ClinPred

0.82

GERP RS

0.35

Varity_R

0.74

gMVP

0.64

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