rs34016249

Variant names:

• chr15-78962183-G-A
• rs34016249
• NM_001145648.3:c.3735C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001145648.3(RASGRF1):​c.3735C>T​(p.Tyr1245Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00732 in 1,589,592 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (61 hom.)
• Consequence: RASGRF1 NM_001145648.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.300
• Publications: 5 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-78962183-G-A is Benign according to our data. Variant chr15-78962183-G-A is described in ClinVar as Benign. ClinVar VariationId is 773298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.3 with no splicing effect.
• BS2: High AC in GnomAd4 at 929 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.3735C>T	p.Tyr1245Tyr	synonymous	Exon 27 of 27	NP_001139120.1	Q13972-3
	RASGRF1	NM_002891.6		c.3783C>T	p.Tyr1261Tyr	synonymous	Exon 28 of 28	NP_002882.3
	RASGRF1	NM_153815.3		c.1431C>T	p.Tyr477Tyr	synonymous	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.3735C>T	p.Tyr1245Tyr	synonymous	Exon 27 of 27	ENSP00000452781.2	Q13972-3
	RASGRF1	ENST00000394745.3	TSL:1	c.1431C>T	p.Tyr477Tyr	synonymous	Exon 14 of 14	ENSP00000378228.3	Q13972-2
	RASGRF1	ENST00000419573.7	TSL:2	c.3783C>T	p.Tyr1261Tyr	synonymous	Exon 28 of 28	ENSP00000405963.3	Q13972-1

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 931 AN: 152172 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00952

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00575 AC: 1259 AN: 219078 AF XY: 0.00578

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00352

Gnomad ASJ exome AF: 0.00957

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00584

Gnomad NFE exome AF: 0.00854

Gnomad OTH exome AF: 0.00649

GnomAD4 exome AF: 0.00745 AC: 10703 AN: 1437302 Hom.: 61 Cov.: 30 AF XY: 0.00737 AC XY: 5258 AN XY: 713206

African (AFR) AF: 0.00122 AC: 40 AN: 32918

American (AMR) AF: 0.00361 AC: 156 AN: 43186

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 260 AN: 25656

East Asian (EAS) AF: 0.000256 AC: 10 AN: 39118

South Asian (SAS) AF: 0.00332 AC: 276 AN: 83240

European-Finnish (FIN) AF: 0.00742 AC: 387 AN: 52134

Middle Eastern (MID) AF: 0.00592 AC: 34 AN: 5742

European-Non Finnish (NFE) AF: 0.00834 AC: 9136 AN: 1095946

Other (OTH) AF: 0.00681 AC: 404 AN: 59362

GnomAD4 genome AF: 0.00610 AC: 929 AN: 152290 Hom.: 7 Cov.: 32 AF XY: 0.00608 AC XY: 453 AN XY: 74472

African (AFR) AF: 0.00137 AC: 57 AN: 41558

American (AMR) AF: 0.00490 AC: 75 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00952 AC: 648 AN: 68032

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00797 Hom.: 19

Bravo AF: 0.00547

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.3
DANN	Benign	0.44
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism

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: rs34016249; hg19: chr15-79254525;