NM_001145648.3:c.3737A>G

Variant names:

• chr15-78962181-T-C
• rs551490924
• NM_001145648.3:c.3737A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001145648.3(RASGRF1):​c.3737A>G​(p.Glu1246Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,589,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RASGRF1 NM_001145648.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14631754).
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145648.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRF1	NM_001145648.3	MANE Select	c.3737A>G	p.Glu1246Gly	missense	Exon 27 of 27	NP_001139120.1	Q13972-3
	RASGRF1	NM_002891.6		c.3785A>G	p.Glu1262Gly	missense	Exon 28 of 28	NP_002882.3
	RASGRF1	NM_153815.3		c.1433A>G	p.Glu478Gly	missense	Exon 14 of 14	NP_722522.1	Q13972-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRF1	ENST00000558480.7	TSL:2 MANE Select	c.3737A>G	p.Glu1246Gly	missense	Exon 27 of 27	ENSP00000452781.2	Q13972-3
	RASGRF1	ENST00000394745.3	TSL:1	c.1433A>G	p.Glu478Gly	missense	Exon 14 of 14	ENSP00000378228.3	Q13972-2
	RASGRF1	ENST00000419573.7	TSL:2	c.3785A>G	p.Glu1262Gly	missense	Exon 28 of 28	ENSP00000405963.3	Q13972-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000365 AC: 8 AN: 218920 AF XY: 0.0000425

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 FIN exome AF: 0.0000527

Gnomad NFE exome AF: 0.0000739

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000160 AC: 23 AN: 1437326 Hom.: 0 Cov.: 30 AF XY: 0.0000168 AC XY: 12 AN XY: 713232

African (AFR) AF: 0.00 AC: 0 AN: 32890

American (AMR) AF: 0.00 AC: 0 AN: 43210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25652

East Asian (EAS) AF: 0.00 AC: 0 AN: 39128

South Asian (SAS) AF: 0.00 AC: 0 AN: 83212

European-Finnish (FIN) AF: 0.0000575 AC: 3 AN: 52130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000182 AC: 20 AN: 1095998

Other (OTH) AF: 0.00 AC: 0 AN: 59362

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.080
Sift	Benign	0.050	D
Sift4G	Benign	0.11	T
Vest4		0.074
MVP		0.19
MPC		0.68
ClinPred		0.20	T
GERP RS		4.0
Varity_R		0.21
gMVP		0.52

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

Other links and lift over

dbSNP: rs551490924; hg19: chr15-79254523;