15-79003850-C-T

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.2401G>A(p.Asp801Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,254 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (4 hom.)
• Consequence: RASGRF1 NM_001145648.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.34

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=0.0033151507).
• BP6: Variant 15-79003850-C-T is Benign according to our data. Variant chr15-79003850-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 790325.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRF1	NM_001145648.3	c.2401G>A	p.Asp801Asn	missense_variant	15/27	ENST00000558480.7
LOC105370917	XR_932518.3	n.348-1997C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRF1	ENST00000558480.7	c.2401G>A	p.Asp801Asn	missense_variant	15/27	2	NM_001145648.3	P1
RASGRF1	ENST00000394745.3	c.97G>A	p.Asp33Asn	missense_variant	2/14	1
RASGRF1	ENST00000560334.5	n.2271G>A		non_coding_transcript_exon_variant	14/24	1
RASGRF1	ENST00000419573.7	c.2449G>A	p.Asp817Asn	missense_variant	16/28	2

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152166 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00193 AC: 484 AN: 250328 Hom.: 2 AF XY: 0.00182 AC XY: 246 AN XY: 135330

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00739

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.000939

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00246 AC: 3592 AN: 1460972 Hom.: 4 Cov.: 33 AF XY: 0.00232 AC XY: 1686 AN XY: 726740

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00717

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00281

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74462

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00268 Hom.: 5

Bravo AF: 0.00171

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00189 AC: 230

EpiCase AF: 0.00311

EpiControl AF: 0.00249

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Benign	0.91
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0033	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.020	N;N;N
Sift	Uncertain	0.027	D;T;D
Sift4G	Benign	0.40	T;T;T
Vest4		0.22
MVP		0.25
MPC		0.57
ClinPred		0.030	T
GERP RS		5.0
Varity_R		0.078
gMVP		0.18

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: rs113161554; hg19: chr15-79296192;