5-81092803-T-A

Variant names:

• chr5-81092803-T-A
• NM_006909.3:c.1393T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006909.3(RASGRF2):​c.1393T>A​(p.Ser465Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASGRF2 NM_006909.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

Genes affected

RASGRF2 (HGNC:9876): (Ras protein specific guanine nucleotide releasing factor 2) RAS GTPases cycle between an inactive GDP-bound state and an active GTP-bound state. This gene encodes a calcium-regulated nucleotide exchange factor activating both RAS and RAS-related protein, RAC1, through the exchange of bound GDP for GTP, thereby, coordinating the signaling of distinct mitogen-activated protein kinase pathways. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21114218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRF2	NM_006909.3	c.1393T>A	p.Ser465Thr	missense_variant, splice_region_variant	Exon 10 of 27	ENST00000265080.9	NP_008840.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRF2	ENST00000265080.9	c.1393T>A	p.Ser465Thr	missense_variant, splice_region_variant	Exon 10 of 27	1	NM_006909.3	ENSP00000265080.4
RASGRF2	ENST00000503795.1	n.1393T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 28	1		ENSP00000421771.1
RASGRF2	ENST00000512186.1	n.-113T>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1393T>A (p.S465T) alteration is located in exon 1 (coding exon 1) of the RASGRF2 gene. This alteration results from a T to A substitution at nucleotide position 1393, causing the serine (S) at amino acid position 465 to be replaced by a threonine (T). 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	0.076
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.062
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.035
Sift	Benign	0.32	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.30		Loss of disorder (P = 0.0921);
MVP		0.17
MPC		0.77
ClinPred		0.73	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr5-80388622;