chr2-33516640-T-C

Variant names:

• chr2-33516640-T-C
• rs528323494
• NM_001139488.2:c.169T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001139488.2(RASGRP3):​c.169T>C​(p.Cys57Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,378,664 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C57G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22083133).

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.169T>C	p.Cys57Arg	missense	Exon 4 of 18	NP_001132960.1	Q8IV61-1
	RASGRP3	NM_001349975.2		c.169T>C	p.Cys57Arg	missense	Exon 6 of 20	NP_001336904.1	Q8IV61-1
	RASGRP3	NM_001349976.2		c.169T>C	p.Cys57Arg	missense	Exon 4 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.169T>C	p.Cys57Arg	missense	Exon 4 of 18	ENSP00000384192.3	Q8IV61-1
	RASGRP3	ENST00000402538.8	TSL:1	c.169T>C	p.Cys57Arg	missense	Exon 5 of 19	ENSP00000385886.3	Q8IV61-1
	RASGRP3	ENST00000407811.5	TSL:1	c.169T>C	p.Cys57Arg	missense	Exon 3 of 17	ENSP00000383917.1	Q8IV61-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000580 AC: 8 AN: 1378664 Hom.: 0 Cov.: 27 AF XY: 0.00000875 AC XY: 6 AN XY: 685582

African (AFR) AF: 0.00 AC: 0 AN: 31826

American (AMR) AF: 0.00 AC: 0 AN: 40046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25276

East Asian (EAS) AF: 0.00 AC: 0 AN: 38612

South Asian (SAS) AF: 0.00 AC: 0 AN: 80556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00000764 AC: 8 AN: 1047324

Other (OTH) AF: 0.00 AC: 0 AN: 57676

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.080
Sift	Benign	0.21	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.49
MutPred		0.40		Gain of disorder (P = 0.0265)
MVP		0.45
MPC		0.22
ClinPred		0.44	T
GERP RS		5.8
Varity_R		0.42
gMVP		0.36
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs528323494; hg19: chr2-33741707;