Genetic Variant RASGRP3:p.Ile301Thr (chr2-33527231-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001139488.2(RASGRP3):c.902T>C(p.Ile301Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I301I) has been classified as Likely benign.

Frequency

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

Consequence

RASGRP3
NM_001139488.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Publications

0 publications found

Variant links:

Genes affected

RASGRP3 (HGNC:14545): (RAS guanyl releasing protein 3) The protein encoded by this gene is a guanine nucleotide exchange factor that activates the oncogenes HRAS and RAP1A. Defects in this gene have been associated with systemic lupus erythematosus and several cancers. [provided by RefSeq, Mar 2017]

RASGRP3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001139488.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGRP3	NM_001139488.2	MANE Select	c.902T>C	p.Ile301Thr	missense	Exon 10 of 18	NP_001132960.1	Q8IV61-1
RASGRP3	NM_001349975.2		c.902T>C	p.Ile301Thr	missense	Exon 12 of 20	NP_001336904.1	Q8IV61-1
RASGRP3	NM_001349976.2		c.902T>C	p.Ile301Thr	missense	Exon 10 of 18	NP_001336905.1	Q8IV61-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGRP3	ENST00000403687.8	TSL:1 MANE Select	c.902T>C	p.Ile301Thr	missense	Exon 10 of 18	ENSP00000384192.3	Q8IV61-1
RASGRP3	ENST00000402538.8	TSL:1	c.902T>C	p.Ile301Thr	missense	Exon 11 of 19	ENSP00000385886.3	Q8IV61-1
RASGRP3	ENST00000407811.5	TSL:1	c.902T>C	p.Ile301Thr	missense	Exon 9 of 17	ENSP00000383917.1	Q8IV61-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249180

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

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

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-0.48

MutationAssessor

Pathogenic

2.9

PhyloP100

8.0

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.94

MutPred

0.68

Loss of catalytic residue at L306 (P = 0.0281)

MVP

0.84

MPC

0.41

ClinPred

0.97

GERP RS

5.7

Varity_R

0.75

gMVP

0.71

Mutation Taster

=38/62

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over