15-78998745-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001145648.3(RASGRF1):c.2827C>T(p.Arg943Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,750 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: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RASGRF1 NM_001145648.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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]

LOC105370917 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RASGRF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRF1	NM_001145648.3	c.2827C>T	p.Arg943Cys	missense_variant	18/27	ENST00000558480.7
LOC105370917	XR_932518.3	n.168G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRF1	ENST00000558480.7	c.2827C>T	p.Arg943Cys	missense_variant	18/27	2	NM_001145648.3	P1
RASGRF1	ENST00000394745.3	c.523C>T	p.Arg175Cys	missense_variant	5/14	1
RASGRF1	ENST00000560334.5	n.2697C>T		non_coding_transcript_exon_variant	17/24	1
RASGRF1	ENST00000419573.7	c.2875C>T	p.Arg959Cys	missense_variant	19/28	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251432 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

Gnomad AFR exome AF: 0.00

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: 0.00000342 AC: 5 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.2875C>T (p.R959C) alteration is located in exon 19 (coding exon 19) of the RASGRF1 gene. This alteration results from a C to T substitution at nucleotide position 2875, causing the arginine (R) at amino acid position 959 to be replaced by a cysteine (C). 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	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.81
MVP		0.64
MPC		1.8
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.65
gMVP		0.80

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

Other links and lift over

dbSNP: rs746752222; hg19: chr15-79291087; COSMIC: COSV67249837; COSMIC: COSV67249837;