Variant 5-81085865-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The ENST00000265080.9(RASGRF2):c.1225A>G(p.Arg409Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

RASGRF2
ENST00000265080.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79

Variant links:

Genes affected

RASGRF2 (HGNC:9876): (Ras protein specific guanine nucleotide releasing factor 2) RAS GTPases cycle between an inactive GDP-bound state and an active GTP-bound state. This gene encodes a calcium-regulated nucleotide exchange factor activating both RAS and RAS-related protein, RAC1, through the exchange of bound GDP for GTP, thereby, coordinating the signaling of distinct mitogen-activated protein kinase pathways. [provided by RefSeq, Oct 2011]

RASGRF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.861

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRF2	NM_006909.3 linkuse as main transcript	c.1225A>G	p.Arg409Gly	missense_variant	8/27	ENST00000265080.9	NP_008840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RASGRF2	ENST00000265080.9 linkuse as main transcript	c.1225A>G	p.Arg409Gly	missense_variant	8/27	1	NM_006909.3	ENSP00000265080	P1
RASGRF2	ENST00000503795.1 linkuse as main transcript	c.1225A>G	p.Arg409Gly	missense_variant, NMD_transcript_variant	8/28	1		ENSP00000421771
RASGRF2	ENST00000638442.1 linkuse as main transcript	c.1225A>G	p.Arg409Gly	missense_variant	8/10	5		ENSP00000491428
RASGRF2	ENST00000502677.1 linkuse as main transcript	n.1150A>G		non_coding_transcript_exon_variant	5/7	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250166

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135316

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000534

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000629

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000818

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000965

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

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

Apr 17, 2023

The c.1225A>G (p.R409G) alteration is located in exon 1 (coding exon 1) of the RASGRF2 gene. This alteration results from a A to G substitution at nucleotide position 1225, causing the arginine (R) at amino acid position 409 to be replaced by a glycine (G). 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

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

-0.017

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.7

D;.

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.90

MVP

0.82

MPC

2.2

ClinPred

0.96

GERP RS

5.6

Varity_R

0.85

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over