19-11394430-C-T

Variant names:

• chr19-11394430-C-T
• rs142089258
• NM_001035223.4:c.2105G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001035223.4(RGL3):​c.2105G>A​(p.Arg702Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R702W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: RGL3 NM_001035223.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.59
• Publications: 5 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06826696).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001035223.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGL3	NM_001035223.4	MANE Select	c.2105G>A	p.Arg702Gln	missense	Exon 19 of 19	NP_001030300.3	Q3MIN7-1
	RGL3	NM_001161616.3		c.2123G>A	p.Arg708Gln	missense	Exon 19 of 19	NP_001155088.2	Q3MIN7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGL3	ENST00000380456.8	TSL:1 MANE Select	c.2105G>A	p.Arg702Gln	missense	Exon 19 of 19	ENSP00000369823.3	Q3MIN7-1
	RGL3	ENST00000393423.7	TSL:1	c.2123G>A	p.Arg708Gln	missense	Exon 19 of 19	ENSP00000377075.3	Q3MIN7-2
	RGL3	ENST00000920283.1		c.2144G>A	p.Arg715Gln	missense	Exon 19 of 19	ENSP00000590342.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151872 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251472 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461780 Hom.: 0 Cov.: 30 AF XY: 0.0000756 AC XY: 55 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000980 AC: 109 AN: 1111926

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151872 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74170

African (AFR) AF: 0.0000242 AC: 1 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.4
DANN	Benign	0.79
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.6
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.0080
Sift	Benign	0.48	T
Sift4G	Benign	0.53	T
Vest4		0.13
MVP		0.085
MPC		0.12
ClinPred		0.038	T
GERP RS		-5.2
gMVP		0.12
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs142089258; hg19: chr19-11505106; COSMIC: COSV66509500; COSMIC: COSV66509500;