chr12-47748853-C-G

Variant names:

• chr12-47748853-C-G
• rs12422983
• NM_001098531.4:c.1120G>C

Variant summary

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

The NM_001098531.4(RAPGEF3):​c.1120G>C​(p.Gly374Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAPGEF3 NM_001098531.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.711
• Publications: 28 publications found

Genes affected

RAPGEF3 (HGNC:16629): (Rap guanine nucleotide exchange factor 3) Enables guanyl-nucleotide exchange factor activity and protein domain specific binding activity. Involved in several processes, including positive regulation of protein modification process; regulation of actin cytoskeleton organization; and regulation of syncytium formation by plasma membrane fusion. Located in filopodium; lamellipodium; and microvillus. Colocalizes with cortical actin cytoskeleton and plasma membrane. Biomarker of congestive heart failure. [provided by Alliance of Genome Resources, Apr 2022]

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=0.16340852).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098531.4. 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
	RAPGEF3	NM_001098531.4	MANE Select	c.1120G>C	p.Gly374Arg	missense	Exon 11 of 28	NP_001092001.2	O95398-1
	RAPGEF3	NM_001098532.2		c.994G>C	p.Gly332Arg	missense	Exon 10 of 27	NP_001092002.1	O95398
	RAPGEF3	NM_006105.5		c.994G>C	p.Gly332Arg	missense	Exon 11 of 28	NP_006096.2	Q99777

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEF3	ENST00000449771.7	TSL:2 MANE Select	c.1120G>C	p.Gly374Arg	missense	Exon 11 of 28	ENSP00000395708.2	O95398-1
	RAPGEF3	ENST00000389212.7	TSL:2	c.1120G>C	p.Gly374Arg	missense	Exon 12 of 29	ENSP00000373864.3	O95398-1
	RAPGEF3	ENST00000549151.5	TSL:5	c.994G>C	p.Gly332Arg	missense	Exon 11 of 28	ENSP00000448619.1	O95398-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 6250

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.71
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.026	D
Sift4G	Benign	0.067	T
Polyphen		0.90	P
Vest4		0.28
MutPred		0.39		Gain of catalytic residue at P378 (P = 0)
MVP		0.68
MPC		0.27
ClinPred		0.13	T
GERP RS		3.3
Varity_R		0.065
gMVP		0.33
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12422983; hg19: chr12-48142636;