2-33558687-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001139488.2(RASGRP3):c.1721T>C(p.Phe574Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,636 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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-AS1 (HGNC:):

FAM98A (HGNC:24520): (family with sequence similarity 98 member A) Enables protein methyltransferase activity. Involved in positive regulation of cell population proliferation; positive regulation of gene expression; and protein methylation. Predicted to be part of tRNA-splicing ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRP3	NM_001139488.2	c.1721T>C	p.Phe574Ser	missense_variant	17/18	ENST00000403687.8
RASGRP3-AS1	NR_146505.1	n.2497-3373A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRP3	ENST00000403687.8	c.1721T>C	p.Phe574Ser	missense_variant	17/18	1	NM_001139488.2	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449636 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 28, 2023

The c.1721T>C (p.F574S) alteration is located in exon 17 (coding exon 15) of the RASGRP3 gene. This alteration results from a T to C substitution at nucleotide position 1721, causing the phenylalanine (F) at amino acid position 574 to be replaced by a serine (S). 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	0.61
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.061	D
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.75
MutPred		0.36		Gain of glycosylation at F574 (P = 0.0097);Gain of glycosylation at F574 (P = 0.0097);.;
MVP		0.92
MPC		0.73
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.73
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-33783754; COSMIC: COSV67822693;