Variant 19-11397553-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001035223.4(RGL3):c.1791G>T(p.Leu597Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,604,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RGL3
NM_001035223.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0390

Variant links:

Genes affected

RGL3 (HGNC:30282): (ral guanine nucleotide dissociation stimulator like 3) Predicted to enable guanyl-nucleotide exchange factor activity and small GTPase binding activity. Predicted to be involved in positive regulation of GTPase activity and small GTPase mediated signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

RGL3 links:

RGL3 (HGNC:):

RGL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGL3	NM_001035223.4 linkuse as main transcript	c.1791G>T	p.Leu597Phe	missense_variant	17/19	ENST00000380456.8	NP_001030300.3	Q3MIN7A0A0A0MRX4
RGL3	NM_001161616.3 linkuse as main transcript	c.1809G>T	p.Leu603Phe	missense_variant	17/19		NP_001155088.2	Q3MIN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGL3	ENST00000380456.8 linkuse as main transcript	c.1791G>T	p.Leu597Phe	missense_variant	17/19	1	NM_001035223.4	ENSP00000369823.3		A0A0A0MRX4

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000131

AC:

AN:

229672

Hom.:

AF XY:

0.00

AC XY:

AN XY:

125138

show subpopulations

Gnomad AFR exome

AF:

0.0000731

Gnomad AMR exome

AF:

0.0000613

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

AF:

0.00000344

AC:

AN:

1452766

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722008

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.0000694

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

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 07, 2024

The c.1809G>T (p.L603F) alteration is located in exon 17 (coding exon 17) of the RGL3 gene. This alteration results from a G to T substitution at nucleotide position 1809, causing the leucine (L) at amino acid position 603 to be replaced by a phenylalanine (F). 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

0.068

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.016

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.35

T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.089

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.96

N;N

REVEL

Benign

0.028

Sift

Benign

0.13

T;T

Sift4G

Benign

0.75

T;T

Vest4

0.034

MutPred

0.22

Loss of catalytic residue at L597 (P = 0.0624);.;

MVP

0.18

MPC

0.11

ClinPred

0.32

GERP RS

0.38

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.38

Position offset: -12

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