15-79003846-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_001145648.3(RASGRF1):c.2405C>T(p.Thr802Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000609 in 1,612,894 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: RASGRF1 NM_001145648.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.418

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RASGRF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0039519668).
• BP6: Variant 15-79003846-G-A is Benign according to our data. Variant chr15-79003846-G-A is described in ClinVar as [Benign]. Clinvar id is 711632.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 473 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRF1	NM_001145648.3	c.2405C>T	p.Thr802Met	missense_variant	15/27	ENST00000558480.7
LOC105370917	XR_932518.3	n.348-2001G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRF1	ENST00000558480.7	c.2405C>T	p.Thr802Met	missense_variant	15/27	2	NM_001145648.3	P1
RASGRF1	ENST00000394745.3	c.101C>T	p.Thr34Met	missense_variant	2/14	1
RASGRF1	ENST00000560334.5	n.2275C>T		non_coding_transcript_exon_variant	14/24	1
RASGRF1	ENST00000419573.7	c.2453C>T	p.Thr818Met	missense_variant	16/28	2

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152202 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000912 AC: 228 AN: 250040 Hom.: 1 AF XY: 0.000629 AC XY: 85 AN XY: 135184

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.000812

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000348 AC: 509 AN: 1460574 Hom.: 2 Cov.: 33 AF XY: 0.000289 AC XY: 210 AN XY: 726534

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00311 AC: 473 AN: 152320 Hom.: 4 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74490

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000956 Hom.: 2

Bravo AF: 0.00333

ESP6500AA AF: 0.0114 AC: 50

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00107 AC: 130

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.50
Dann	Benign	0.88
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.59	T;T;T
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.10	T;T;T
Vest4		0.11
MVP		0.15
MPC		0.64
ClinPred		0.0010	T
GERP RS		-0.86
Varity_R		0.022
gMVP		0.22

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: rs79149121; hg19: chr15-79296188; COSMIC: COSV67250206;