2-33519952-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001139488.2(RASGRP3):c.174G>A(p.Met58Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000442 in 1,608,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: RASGRP3 NM_001139488.2 missense, splice_region
• Scores: Splicing: ADA: 0.005230
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.242

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13115185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRP3	NM_001139488.2	c.174G>A	p.Met58Ile	missense_variant, splice_region_variant	5/18	ENST00000403687.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRP3	ENST00000403687.8	c.174G>A	p.Met58Ile	missense_variant, splice_region_variant	5/18	1	NM_001139488.2	P5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000249 AC: 6 AN: 241036 Hom.: 0 AF XY: 0.0000307 AC XY: 4 AN XY: 130412

Gnomad AFR exome AF: 0.0000680

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000570

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000426 AC: 62 AN: 1455858 Hom.: 0 Cov.: 30 AF XY: 0.0000428 AC XY: 31 AN XY: 723548

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000451

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74418

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000493 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The c.174G>A (p.M58I) alteration is located in exon 5 (coding exon 3) of the RASGRP3 gene. This alteration results from a G to A substitution at nucleotide position 174, causing the methionine (M) at amino acid position 58 to be replaced by an isoleucine (I). 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	Benign	0.17
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	14
Dann	Benign	0.84
DEOGEN2	Benign	0.22	T;.;T;.;.;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.83	N;.;N;.;.;.;N
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.64	N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.34	T;T;T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.;.
Vest4		0.25
MutPred		0.64		Loss of phosphorylation at T63 (P = 0.1626);Loss of phosphorylation at T63 (P = 0.1626);Loss of phosphorylation at T63 (P = 0.1626);Loss of phosphorylation at T63 (P = 0.1626);Loss of phosphorylation at T63 (P = 0.1626);Loss of phosphorylation at T63 (P = 0.1626);Loss of phosphorylation at T63 (P = 0.1626);
MVP		0.72
MPC		0.12
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.046
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0052
SpliceAI score (max)		0.010		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: rs200007507; hg19: chr2-33745019; COSMIC: COSV67822907; COSMIC: COSV67822907;