chr4-81434680-C-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_152545.3(RASGEF1B):c.1159G>T(p.Gly387Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000055 in 1,455,250 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: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
RASGEF1B
NM_152545.3 missense
NM_152545.3 missense
Scores
11
4
2
Clinical Significance
Conservation
PhyloP100: 5.86
Genes affected
RASGEF1B (HGNC:24881): (RasGEF domain family member 1B) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity and small GTPase mediated signal transduction. Predicted to be located in early endosome; late endosome; and midbody. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.954
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RASGEF1B | NM_152545.3 | c.1159G>T | p.Gly387Cys | missense_variant | 11/14 | ENST00000264400.7 | |
RASGEF1B | NM_001300735.2 | c.1156G>T | p.Gly386Cys | missense_variant | 11/14 | ||
RASGEF1B | NM_001300736.2 | c.1033G>T | p.Gly345Cys | missense_variant | 10/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RASGEF1B | ENST00000264400.7 | c.1159G>T | p.Gly387Cys | missense_variant | 11/14 | 2 | NM_152545.3 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251174Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135760
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GnomAD4 exome AF: 0.00000550 AC: 8AN: 1455250Hom.: 0 Cov.: 27 AF XY: 0.00000552 AC XY: 4AN XY: 724490
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ExAC
?
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1
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 | Jan 06, 2023 | The c.1159G>T (p.G387C) alteration is located in exon 11 (coding exon 10) of the RASGEF1B gene. This alteration results from a G to T substitution at nucleotide position 1159, causing the glycine (G) at amino acid position 387 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D;D
Sift4G
Uncertain
D;D;.;D;.
Polyphen
D;D;.;D;.
Vest4
MutPred
0.88
.;Loss of catalytic residue at L392 (P = 0.1973);.;.;.;
MVP
MPC
1.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at