5-180119376-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_175062.4(RASGEF1C):​c.877G>A​(p.Gly293Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,970 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 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RASGEF1C
NM_175062.4 missense

Scores

5
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.62
Variant links:
Genes affected
RASGEF1C (HGNC:27400): (RasGEF domain family member 1C) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity and small GTPase mediated signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RASGEF1CNM_175062.4 linkc.877G>A p.Gly293Ser missense_variant Exon 8 of 14 ENST00000361132.9 NP_778232.2 Q8N431-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RASGEF1CENST00000361132.9 linkc.877G>A p.Gly293Ser missense_variant Exon 8 of 14 1 NM_175062.4 ENSP00000354963.4 Q8N431-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251418
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461774
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152196
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.877G>A (p.G293S) alteration is located in exon 8 (coding exon 7) of the RASGEF1C gene. This alteration results from a G to A substitution at nucleotide position 877, causing the glycine (G) at amino acid position 293 to be replaced by a serine (S). 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
0.96
BayesDel_addAF
Benign
-0.031
T
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;.;T;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
.;D;D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Pathogenic
0.82
D;D;D;D
MetaSVM
Benign
-0.78
T
MutationAssessor
Uncertain
2.3
M;.;M;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.4
D;.;D;D
REVEL
Uncertain
0.29
Sift
Uncertain
0.0020
D;.;D;D
Sift4G
Benign
0.071
T;T;T;T
Polyphen
1.0
D;.;D;.
Vest4
0.78
MutPred
0.46
Loss of catalytic residue at I292 (P = 0.2022);.;Loss of catalytic residue at I292 (P = 0.2022);.;
MVP
0.66
MPC
0.84
ClinPred
0.99
D
GERP RS
4.4
Varity_R
0.80
gMVP
0.58

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: rs755415164; hg19: chr5-179546376; COSMIC: COSV63179542; COSMIC: COSV63179542; API