19-11397558-C-A

Variant names:

• chr19-11397558-C-A
• rs774088081
• NM_001035223.4:c.1786G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001035223.4(RGL3):​c.1786G>T​(p.Ala596Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A596T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RGL3 NM_001035223.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0260
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1786G>T	p.Ala596Ser	missense	Exon 17 of 19	NP_001030300.3	Q3MIN7-1
	RGL3	NM_001161616.3		c.1804G>T	p.Ala602Ser	missense	Exon 17 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.1786G>T	p.Ala596Ser	missense	Exon 17 of 19	ENSP00000369823.3	Q3MIN7-1
	RGL3	ENST00000393423.7	TSL:1	c.1804G>T	p.Ala602Ser	missense	Exon 17 of 19	ENSP00000377075.3	Q3MIN7-2
	RGL3	ENST00000920283.1		c.1825G>T	p.Ala609Ser	missense	Exon 17 of 19	ENSP00000590342.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446826 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718562

African (AFR) AF: 0.00 AC: 0 AN: 33140

American (AMR) AF: 0.0000237 AC: 1 AN: 42166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25812

East Asian (EAS) AF: 0.00 AC: 0 AN: 39138

South Asian (SAS) AF: 0.00 AC: 0 AN: 85024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104218

Other (OTH) AF: 0.00 AC: 0 AN: 59810

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.5
DANN	Benign	0.19
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.026
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.19
MutPred		0.19		Gain of phosphorylation at A596 (P = 0.0061)
MVP		0.085
MPC		0.095
ClinPred		0.097	T
GERP RS		-0.42
gMVP		0.34
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs774088081; hg19: chr19-11508234;