dbSNP rs1007298: RGL4:p.Val378Asp (chr22-23696660-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153615.2(RGL4):c.1133T>A(p.Val378Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V378A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RGL4
NM_153615.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.872

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:):

GUSBP11 links:

ENSG00000272578 (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]

ENSG00000272578 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10193297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGL4	NM_153615.2 link	c.1133T>A	p.Val378Asp	missense_variant	Exon 7 of 11	ENST00000290691.10	NP_705843.1	Q8IZJ4-1
RGL4	NM_001329424.3 link	c.1133T>A	p.Val378Asp	missense_variant	Exon 7 of 12		NP_001316353.1	Q8IZJ4Q3ZCN2
RGL4	NM_001329425.2 link	c.-5T>A		5_prime_UTR_variant	Exon 2 of 6		NP_001316354.1	Q8IZJ4
GUSBP11	NR_024448.2 link	n.1163-1143A>T		intron_variant	Intron 7 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGL4	ENST00000290691.10 link	c.1133T>A	p.Val378Asp	missense_variant	Exon 7 of 11	1	NM_153615.2	ENSP00000290691.5		Q8IZJ4-1
RGL4	ENST00000441897.5 link	n.1300T>A		non_coding_transcript_exon_variant	Exon 10 of 14	2		ENSP00000396252.1		E9PH21

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249848

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.0000619

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1461138

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.028

.;.;.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.73

T;T;T;T;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.10

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.090

.;.;.;N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.5

N;.;.;N;N

REVEL

Benign

0.057

Sift

Benign

0.12

T;.;.;D;T

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

0.015

.;.;.;B;.

Vest4

0.30

MutPred

0.48

.;.;.;Gain of disorder (P = 0.051);Gain of disorder (P = 0.051);

MVP

0.34

MPC

0.15

ClinPred

0.19

GERP RS

-0.41

Varity_R

0.19

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over