Genetic Variant NM_001139488.2:c.349C>G (chr2-33520665-C-G) – 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.349C>G(p.Leu117Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L117F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RASGRP3
NM_001139488.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.74

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, 0.879

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.349C>G	p.Leu117Val	missense	Exon 6 of 18	NP_001132960.1	Q8IV61-1
RASGRP3	NM_001349975.2		c.349C>G	p.Leu117Val	missense	Exon 8 of 20	NP_001336904.1	Q8IV61-1
RASGRP3	NM_001349976.2		c.349C>G	p.Leu117Val	missense	Exon 6 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.349C>G	p.Leu117Val	missense	Exon 6 of 18	ENSP00000384192.3	Q8IV61-1
RASGRP3	ENST00000402538.8	TSL:1	c.349C>G	p.Leu117Val	missense	Exon 7 of 19	ENSP00000385886.3	Q8IV61-1
RASGRP3	ENST00000407811.5	TSL:1	c.349C>G	p.Leu117Val	missense	Exon 5 of 17	ENSP00000383917.1	Q8IV61-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727118

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111844

Other (OTH)

AF:

0.00

AC:

AN:

60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

0.14

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.7

PhyloP100

4.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.32

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.60

MutPred

0.77

Gain of sheet (P = 0.0344)

MVP

0.68

MPC

0.27

ClinPred

0.93

GERP RS

5.6

Varity_R

0.40

gMVP

0.53

Mutation Taster

=87/13

polymorphism

(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

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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