chr15-78962181-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001145648.3(RASGRF1):ā€‹c.3737A>Gā€‹(p.Glu1246Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,589,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

RASGRF1
NM_001145648.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.12
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.14631754).
BS2
High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RASGRF1NM_001145648.3 linkc.3737A>G p.Glu1246Gly missense_variant Exon 27 of 27 ENST00000558480.7 NP_001139120.1 Q8IUU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RASGRF1ENST00000558480.7 linkc.3737A>G p.Glu1246Gly missense_variant Exon 27 of 27 2 NM_001145648.3 ENSP00000452781.2 Q13972-3
RASGRF1ENST00000394745.3 linkc.1433A>G p.Glu478Gly missense_variant Exon 14 of 14 1 ENSP00000378228.3 Q13972-2
RASGRF1ENST00000419573.7 linkc.3785A>G p.Glu1262Gly missense_variant Exon 28 of 28 2 ENSP00000405963.3 Q13972-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000365
AC:
8
AN:
218920
Hom.:
0
AF XY:
0.0000425
AC XY:
5
AN XY:
117718
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:
0.0000527
Gnomad NFE exome
AF:
0.0000739
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000160
AC:
23
AN:
1437326
Hom.:
0
Cov.:
30
AF XY:
0.0000168
AC XY:
12
AN XY:
713232
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:
0.0000575
Gnomad4 NFE exome
AF:
0.0000182
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000670
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000826
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 19, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3785A>G (p.E1262G) alteration is located in exon 28 (coding exon 28) of the RASGRF1 gene. This alteration results from a A to G substitution at nucleotide position 3785, causing the glutamic acid (E) at amino acid position 1262 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
Benign
0.31
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
.;D;.
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.033
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.82
T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
.;L;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-2.9
.;D;D
REVEL
Benign
0.080
Sift
Benign
0.050
.;D;D
Sift4G
Benign
0.11
T;T;T
Vest4
0.074
MVP
0.19
MPC
0.68
ClinPred
0.20
T
GERP RS
4.0
Varity_R
0.21
gMVP
0.52

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.

Other links and lift over

dbSNP: rs551490924; hg19: chr15-79254523; API