Genetic Variant RASGRF1:p.Asn1084Lys (chr15-78985169-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002891.6(RASGRF1):c.3300T>G(p.Asn1100Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RASGRF1
NM_002891.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.32

Publications

16 publications found

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:

ENSG00000177699 (HGNC:):

ENSG00000177699 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046972662).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002891.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RASGRF1	NM_001145648.3	MANE Select	c.3252T>G	p.Asn1084Lys	missense	Exon 23 of 27	NP_001139120.1
RASGRF1	NM_002891.6		c.3300T>G	p.Asn1100Lys	missense	Exon 24 of 28	NP_002882.3
RASGRF1	NM_153815.3		c.948T>G	p.Asn316Lys	missense	Exon 10 of 14	NP_722522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RASGRF1	ENST00000558480.7	TSL:2 MANE Select	c.3252T>G	p.Asn1084Lys	missense	Exon 23 of 27	ENSP00000452781.2
RASGRF1	ENST00000394745.3	TSL:1	c.948T>G	p.Asn316Lys	missense	Exon 10 of 14	ENSP00000378228.3
RASGRF1	ENST00000560334.5	TSL:1	n.3122T>G		non_coding_transcript_exon	Exon 22 of 24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251182

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110470

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.010

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.074

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.82

M_CAP

Benign

0.0071

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

PhyloP100

-2.3

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.40

REVEL

Benign

0.021

Sift

Benign

0.53

Sift4G

Benign

0.62

Vest4

0.27

MVP

0.18

MPC

0.67

ClinPred

0.029

GERP RS

-7.9

Varity_R

0.054

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over