2-33527231-T-C

Variant names:

• chr2-33527231-T-C
• rs1204080133
• NM_001139488.2:c.902T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRP3	NM_001139488.2	c.902T>C	p.Ile301Thr	missense_variant	Exon 10 of 18	ENST00000403687.8	NP_001132960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASGRP3	ENST00000403687.8	c.902T>C	p.Ile301Thr	missense_variant	Exon 10 of 18	1	NM_001139488.2	ENSP00000384192.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249180 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135182

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 SAS 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.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.902T>C (p.I301T) alteration is located in exon 10 (coding exon 8) of the RASGRP3 gene. This alteration results from a T to C substitution at nucleotide position 902, causing the isoleucine (I) at amino acid position 301 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	2.9	M;M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.68		Loss of catalytic residue at L306 (P = 0.0281);Loss of catalytic residue at L306 (P = 0.0281);Loss of catalytic residue at L306 (P = 0.0281);
MVP		0.84
MPC		0.41
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.71

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

Other links and lift over

dbSNP: rs1204080133; hg19: chr2-33752298;