chr2-33522043-C-T

Variant names:

• chr2-33522043-C-T
• rs750271899
• NM_001139488.2:c.457C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001139488.2(RASGRP3):​c.457C>T​(p.Pro153Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

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.457C>T	p.Pro153Ser	missense	Exon 7 of 18	NP_001132960.1	Q8IV61-1
	RASGRP3	NM_001349975.2		c.457C>T	p.Pro153Ser	missense	Exon 9 of 20	NP_001336904.1	Q8IV61-1
	RASGRP3	NM_001349976.2		c.457C>T	p.Pro153Ser	missense	Exon 7 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.457C>T	p.Pro153Ser	missense	Exon 7 of 18	ENSP00000384192.3	Q8IV61-1
	RASGRP3	ENST00000402538.8	TSL:1	c.457C>T	p.Pro153Ser	missense	Exon 8 of 19	ENSP00000385886.3	Q8IV61-1
	RASGRP3	ENST00000407811.5	TSL:1	c.457C>T	p.Pro153Ser	missense	Exon 6 of 17	ENSP00000383917.1	Q8IV61-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.32
Sift	Benign	0.050	D
Sift4G	Benign	0.11	T
Polyphen		0.75	P
Vest4		0.84
MutPred		0.66		Loss of loop (P = 0.0986)
MVP		0.84
MPC		0.43
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.42
gMVP		0.78
Mutation Taster		=34/66	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: rs750271899; hg19: chr2-33747110;