10-43203338-C-A

Variant summary

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

The NM_145313.4(RASGEF1A):​c.281G>T​(p.Cys94Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RASGEF1A
NM_145313.4 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.76
Variant links:
Genes affected
RASGEF1A (HGNC:24246): (RasGEF domain family member 1A) Enables guanyl-nucleotide exchange factor activity. Involved in cell migration and positive regulation of Ras protein signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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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, 0.814

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RASGEF1ANM_145313.4 linkc.281G>T p.Cys94Phe missense_variant Exon 3 of 13 ENST00000395810.6 NP_660356.2 Q8N9B8-1
RASGEF1ANM_001282862.2 linkc.305G>T p.Cys102Phe missense_variant Exon 3 of 13 NP_001269791.1 Q8N9B8-2
RASGEF1AXM_005271809.4 linkc.41G>T p.Cys14Phe missense_variant Exon 2 of 12 XP_005271866.1
RASGEF1AXM_011539500.3 linkc.41G>T p.Cys14Phe missense_variant Exon 2 of 12 XP_011537802.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RASGEF1AENST00000395810.6 linkc.281G>T p.Cys94Phe missense_variant Exon 3 of 13 1 NM_145313.4 ENSP00000379155.1 Q8N9B8-1
RASGEF1AENST00000374459.5 linkc.305G>T p.Cys102Phe missense_variant Exon 3 of 13 2 ENSP00000363583.1 Q8N9B8-2
RASGEF1AENST00000395809.5 linkc.281G>T p.Cys94Phe missense_variant Exon 3 of 13 2 ENSP00000379154.1 Q8N9B8-1
RASGEF1AENST00000472864.1 linkn.291G>T non_coding_transcript_exon_variant Exon 2 of 5 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1426782
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
706490
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.281G>T (p.C94F) alteration is located in exon 2 (coding exon 2) of the RASGEF1A gene. This alteration results from a G to T substitution at nucleotide position 281, causing the cysteine (C) at amino acid position 94 to be replaced by a phenylalanine (F). 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
Uncertain
0.34
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Benign
23
DANN
Benign
0.97
DEOGEN2
Benign
0.12
.;T;T
Eigen
Benign
-0.076
Eigen_PC
Benign
-0.023
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.80
T;.;T
M_CAP
Benign
0.052
D
MetaRNN
Pathogenic
0.81
D;D;D
MetaSVM
Benign
-0.95
T
MutationAssessor
Uncertain
2.7
.;M;M
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-7.0
D;D;D
REVEL
Uncertain
0.31
Sift
Benign
0.049
D;D;D
Sift4G
Uncertain
0.0050
D;D;D
Polyphen
0.11
B;B;B
Vest4
0.80
MutPred
0.69
.;Gain of ubiquitination at K98 (P = 0.102);Gain of ubiquitination at K98 (P = 0.102);
MVP
0.73
MPC
1.2
ClinPred
0.93
D
GERP RS
3.5
Varity_R
0.65
gMVP
0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-43698786; API