chr15-78999772-T-G

Position:

chr15-78999772-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001145648.3(RASGRF1):c.2717A>C(p.Lys906Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RASGRF1
NM_001145648.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81

Variant links:

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]

RASGRF1 links:

LOC105370917 (HGNC:):

LOC105370917 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18992367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASGRF1	NM_001145648.3 linkuse as main transcript	c.2717A>C	p.Lys906Thr	missense_variant	17/27	ENST00000558480.7	NP_001139120.1
LOC105370917	XR_932518.3 linkuse as main transcript	n.347+848T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASGRF1	ENST00000558480.7 linkuse as main transcript	c.2717A>C	p.Lys906Thr	missense_variant	17/27	2	NM_001145648.3	ENSP00000452781	P1	Q13972-3
RASGRF1	ENST00000394745.3 linkuse as main transcript	c.413A>C	p.Lys138Thr	missense_variant	4/14	1		ENSP00000378228		Q13972-2
RASGRF1	ENST00000560334.5 linkuse as main transcript	n.2587A>C		non_coding_transcript_exon_variant	16/24	1
RASGRF1	ENST00000419573.7 linkuse as main transcript	c.2765A>C	p.Lys922Thr	missense_variant	18/28	2		ENSP00000405963		Q13972-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152182

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000833

AC:

1206

AN:

1447094

Hom.:

Cov.:

AF XY:

0.000788

AC XY:

568

AN XY:

720394

show subpopulations

Gnomad4 AFR exome

AF:

0.000633

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000175

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000617

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The c.2765A>C (p.K922T) alteration is located in exon 18 (coding exon 18) of the RASGRF1 gene. This alteration results from a A to C substitution at nucleotide position 2765, causing the lysine (K) at amino acid position 922 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.084

.;T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.41

.;N;.

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.32

.;N;N

REVEL

Benign

0.057

Sift

Benign

0.32

.;T;T

Sift4G

Benign

0.91

T;T;T

Vest4

0.49

MVP

0.13

MPC

0.70

ClinPred

0.42

GERP RS

3.2

Varity_R

0.066

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over