2-33524496-C-A

Variant names:

• chr2-33524496-C-A
• rs1366985049
• NM_001139488.2:c.755C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001139488.2(RASGRP3):​c.755C>A​(p.Ser252Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,453,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

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.755C>A	p.Ser252Tyr	missense	Exon 9 of 18	NP_001132960.1	Q8IV61-1
	RASGRP3	NM_001349975.2		c.755C>A	p.Ser252Tyr	missense	Exon 11 of 20	NP_001336904.1	Q8IV61-1
	RASGRP3	NM_001349976.2		c.755C>A	p.Ser252Tyr	missense	Exon 9 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.755C>A	p.Ser252Tyr	missense	Exon 9 of 18	ENSP00000384192.3	Q8IV61-1
	RASGRP3	ENST00000402538.8	TSL:1	c.755C>A	p.Ser252Tyr	missense	Exon 10 of 19	ENSP00000385886.3	Q8IV61-1
	RASGRP3	ENST00000407811.5	TSL:1	c.755C>A	p.Ser252Tyr	missense	Exon 8 of 17	ENSP00000383917.1	Q8IV61-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1453200 Hom.: 0 Cov.: 30 AF XY: 0.00000970 AC XY: 7 AN XY: 721668

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 43798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 83868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1107782

Other (OTH) AF: 0.00 AC: 0 AN: 60114

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.78		Loss of disorder (P = 0.0078)
MVP		0.87
MPC		0.62
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.87
gMVP		0.74
Mutation Taster		=10/90	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

Other links and lift over

dbSNP: rs1366985049; hg19: chr2-33749563;