Variant chr15-78962169-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001145648.3(RASGRF1):c.3749G>A(p.Arg1250Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000334 in 1,585,770 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

RASGRF1
NM_001145648.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.21

Variant links:

Genes affected

RASGRF1 (HGNC:9875): (Ras protein specific guanine nucleotide releasing factor 1) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) similar to the Saccharomyces cerevisiae CDC25 gene product. Functional analysis has demonstrated that this protein stimulates the dissociation of GDP from RAS protein. The studies of the similar gene in mouse suggested that the Ras-GEF activity of this protein in brain can be activated by Ca2+ influx, muscarinic receptors, and G protein beta-gamma subunit. Mouse studies also indicated that the Ras-GEF signaling pathway mediated by this protein may be important for long-term memory. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Mar 2009]

RASGRF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032808065).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRF1	NM_001145648.3 linkuse as main transcript	c.3749G>A	p.Arg1250Gln	missense_variant	27/27	ENST00000558480.7	NP_001139120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGRF1	ENST00000558480.7 linkuse as main transcript	c.3749G>A	p.Arg1250Gln	missense_variant	27/27	2	NM_001145648.3	ENSP00000452781	P1	Q13972-3
RASGRF1	ENST00000394745.3 linkuse as main transcript	c.1445G>A	p.Arg482Gln	missense_variant	14/14	1		ENSP00000378228		Q13972-2
RASGRF1	ENST00000419573.7 linkuse as main transcript	c.3797G>A	p.Arg1266Gln	missense_variant	28/28	2		ENSP00000405963		Q13972-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000549

AC:

AN:

218394

Hom.:

AF XY:

0.0000510

AC XY:

AN XY:

117532

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000853

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000424

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1433676

Hom.:

Cov.:

AF XY:

0.0000351

AC XY:

AN XY:

711650

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00133

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.00000549

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000578

AC:

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 09, 2021

The c.3797G>A (p.R1266Q) alteration is located in exon 28 (coding exon 28) of the RASGRF1 gene. This alteration results from a G to A substitution at nucleotide position 3797, causing the arginine (R) at amino acid position 1266 to be replaced by a glutamine (Q). 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

0.069

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.073

.;T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.033

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.15

.;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

0.50

.;N;N

REVEL

Benign

0.054

Sift

Benign

0.41

.;T;T

Sift4G

Benign

0.67

T;T;T

Vest4

0.23

MVP

0.13

MPC

0.68

ClinPred

0.074

GERP RS

2.0

Varity_R

0.038

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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