Genetic Variant NM_001035223.4:c.1726C>T (chr19-11399875-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001035223.4(RGL3):c.1726C>T(p.Pro576Ser) 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. 15/20 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. P576L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RGL3
NM_001035223.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.481

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056702733).

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.1726C>T	p.Pro576Ser	missense	Exon 16 of 19	NP_001030300.3	Q3MIN7-1
	RGL3	NM_001161616.3		c.1744C>T	p.Pro582Ser	missense	Exon 16 of 19	NP_001155088.2	Q3MIN7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RGL3	ENST00000380456.8	TSL:1 MANE Select	c.1726C>T	p.Pro576Ser	missense	Exon 16 of 19	ENSP00000369823.3	Q3MIN7-1
RGL3	ENST00000393423.7	TSL:1	c.1744C>T	p.Pro582Ser	missense	Exon 16 of 19	ENSP00000377075.3	Q3MIN7-2
RGL3	ENST00000920283.1		c.1765C>T	p.Pro589Ser	missense	Exon 16 of 19	ENSP00000590342.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1355162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

664526

African (AFR)

AF:

0.00

AC:

AN:

29334

American (AMR)

AF:

0.00

AC:

AN:

25932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20360

East Asian (EAS)

AF:

0.00

AC:

AN:

36870

South Asian (SAS)

AF:

0.00

AC:

AN:

68628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5166

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1063260

Other (OTH)

AF:

0.00

AC:

AN:

55680

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0072

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.60

M_CAP

Benign

0.014

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

PhyloP100

0.48

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.010

REVEL

Benign

0.10

Sift

Benign

0.23

Sift4G

Benign

0.61

Vest4

0.13

MutPred

0.20

Gain of phosphorylation at P576 (P = 0.0021)

MVP

0.41

MPC

0.11

ClinPred

0.17

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.46

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over