chr15-78962183-G-A

Position:

• chr15-78962183-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001145648.3(RASGRF1):​c.3735C>T​(p.Tyr1245=) 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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRF1	NM_001145648.3	c.3735C>T	p.Tyr1245=	synonymous_variant	27/27	ENST00000558480.7	NP_001139120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGRF1	ENST00000558480.7	c.3735C>T	p.Tyr1245=	synonymous_variant	27/27	2	NM_001145648.3	ENSP00000452781	P1
RASGRF1	ENST00000394745.3	c.1431C>T	p.Tyr477=	synonymous_variant	14/14	1		ENSP00000378228
RASGRF1	ENST00000419573.7	c.3783C>T	p.Tyr1261=	synonymous_variant	28/28	2		ENSP00000405963

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

GnomAD3 exomes AF: 0.00575 AC: 1259 AN: 219078 Hom.: 8 AF XY: 0.00578 AC XY: 681 AN XY: 117806

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 SAS exome AF: 0.00282

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

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00361

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.000256

Gnomad4 SAS exome AF: 0.00332

Gnomad4 FIN exome AF: 0.00742

Gnomad4 NFE exome AF: 0.00834

Gnomad4 OTH exome AF: 0.00681

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

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.00952

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00844 Hom.: 13

Bravo AF: 0.00547

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.3
DANN	Benign	0.44

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: rs34016249; hg19: chr15-79254525;