chr15-78962172-A-T

Variant summary

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

The NM_001145648.3(RASGRF1):​c.3746T>A​(p.Leu1249His) variant causes a missense change involving the alteration of a conserved nucleotide. 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)

Consequence

RASGRF1
NM_001145648.3 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.98
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]

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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, 0.807

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RASGRF1NM_001145648.3 linkuse as main transcriptc.3746T>A p.Leu1249His missense_variant 27/27 ENST00000558480.7 NP_001139120.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RASGRF1ENST00000558480.7 linkuse as main transcriptc.3746T>A p.Leu1249His missense_variant 27/272 NM_001145648.3 ENSP00000452781 P1Q13972-3
RASGRF1ENST00000394745.3 linkuse as main transcriptc.1442T>A p.Leu481His missense_variant 14/141 ENSP00000378228 Q13972-2
RASGRF1ENST00000419573.7 linkuse as main transcriptc.3794T>A p.Leu1265His missense_variant 28/282 ENSP00000405963 Q13972-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 29, 2023The c.3794T>A (p.L1265H) alteration is located in exon 28 (coding exon 28) of the RASGRF1 gene. This alteration results from a T to A substitution at nucleotide position 3794, causing the leucine (L) at amino acid position 1265 to be replaced by a histidine (H). 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
0.99
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.69
.;D;.
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.81
D;D;D
MetaSVM
Benign
-0.55
T
MutationAssessor
Pathogenic
3.3
.;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.6
.;D;D
REVEL
Uncertain
0.43
Sift
Uncertain
0.0030
.;D;D
Sift4G
Pathogenic
0.0
D;D;D
Vest4
0.66
MVP
0.44
MPC
1.8
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.73
gMVP
0.73

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: chr15-79254514; API