15-79058498-A-G

Variant names:

• chr15-79058498-A-G
• rs3816282
• NM_001145648.3:c.384-17T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145648.3(RASGRF1):​c.384-17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,611,864 control chromosomes in the GnomAD database, including 11,086 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.095 (815 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10271 hom.)
• Consequence: RASGRF1 NM_001145648.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.392
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRF1	NM_001145648.3	c.384-17T>C		intron_variant	Intron 2 of 26	ENST00000558480.7	NP_001139120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRF1	ENST00000558480.7	c.384-17T>C		intron_variant	Intron 2 of 26	2	NM_001145648.3	ENSP00000452781.2
RASGRF1	ENST00000560334.5	n.245-17T>C		intron_variant	Intron 1 of 23	1
RASGRF1	ENST00000419573.7	c.384-17T>C		intron_variant	Intron 2 of 27	2		ENSP00000405963.3

Frequencies

GnomAD3 genomes AF: 0.0951 AC: 14476 AN: 152152 Hom.: 814 Cov.: 33

Gnomad AFR AF: 0.0628

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0664

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.0877

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0976

Gnomad OTH AF: 0.0968

GnomAD2 exomes AF: 0.119 AC: 29896 AN: 250618 AF XY: 0.128

Gnomad AFR exome AF: 0.0625

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.207

Gnomad EAS exome AF: 0.206

Gnomad FIN exome AF: 0.0862

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.109 AC: 159028 AN: 1459594 Hom.: 10271 Cov.: 32 AF XY: 0.113 AC XY: 82034 AN XY: 725624

African (AFR) AF: 0.0627 AC: 2095 AN: 33436

American (AMR) AF: 0.0470 AC: 2099 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 5422 AN: 26102

East Asian (EAS) AF: 0.193 AC: 7657 AN: 39630

South Asian (SAS) AF: 0.241 AC: 20747 AN: 86198

European-Finnish (FIN) AF: 0.0888 AC: 4737 AN: 53360

Middle Eastern (MID) AF: 0.127 AC: 730 AN: 5746

European-Non Finnish (NFE) AF: 0.0973 AC: 108065 AN: 1110136

Other (OTH) AF: 0.124 AC: 7476 AN: 60302

GnomAD4 genome AF: 0.0951 AC: 14480 AN: 152270 Hom.: 815 Cov.: 33 AF XY: 0.0966 AC XY: 7191 AN XY: 74446

African (AFR) AF: 0.0628 AC: 2609 AN: 41572

American (AMR) AF: 0.0663 AC: 1014 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 723 AN: 3472

East Asian (EAS) AF: 0.208 AC: 1077 AN: 5166

South Asian (SAS) AF: 0.244 AC: 1179 AN: 4824

European-Finnish (FIN) AF: 0.0877 AC: 931 AN: 10610

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0976 AC: 6638 AN: 68018

Other (OTH) AF: 0.0977 AC: 206 AN: 2108

Alfa AF: 0.0994 Hom.: 705

Bravo AF: 0.0895

Asia WGS AF: 0.218 AC: 756 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.69
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3816282; hg19: chr15-79350840; COSMIC: COSV69177558;