RASGRP3 p.Phe297Leu

Variant names:

• chr2-33527220-C-A
• NM_001139488.2:c.891C>A
• RASGRP3 p.Phe297Leu

Your query was ambiguous. Multiple possible variants found:

• chr2-33527220-C-A
• chr2-33527220-C-G
• chr2-33527218-T-C
• chr2-33527218-TTC-CTT
• chr2-33527218-TTC-CTA
• chr2-33527218-TTC-CTG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001139488.2(RASGRP3):​c.891C>A​(p.Phe297Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

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]

ACMG classification

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, 0.843

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP3	NM_001139488.2	MANE Select	c.891C>A	p.Phe297Leu	missense	Exon 10 of 18	NP_001132960.1	Q8IV61-1
	RASGRP3	NM_001349975.2		c.891C>A	p.Phe297Leu	missense	Exon 12 of 20	NP_001336904.1	Q8IV61-1
	RASGRP3	NM_001349976.2		c.891C>A	p.Phe297Leu	missense	Exon 10 of 18	NP_001336905.1	Q8IV61-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASGRP3	ENST00000403687.8	TSL:1 MANE Select	c.891C>A	p.Phe297Leu	missense	Exon 10 of 18	ENSP00000384192.3	Q8IV61-1
	RASGRP3	ENST00000402538.8	TSL:1	c.891C>A	p.Phe297Leu	missense	Exon 11 of 19	ENSP00000385886.3	Q8IV61-1
	RASGRP3	ENST00000407811.5	TSL:1	c.891C>A	p.Phe297Leu	missense	Exon 9 of 17	ENSP00000383917.1	Q8IV61-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.023	D
Varity_R		0.92
gMVP		0.69
Mutation Taster		=35/65	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-33752287;