rs12422983

Positions:

• chr12-47748853-C-G
• chr12-47748853-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 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. G374S) has been classified as Likely benign.

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

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]

RAPGEF3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16340852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4	c.1120G>C	p.Gly374Arg	missense_variant	11/28	ENST00000449771.7	NP_001092001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.1120G>C	p.Gly374Arg	missense_variant	11/28	2	NM_001098531.4	ENSP00000395708.2
RAPGEF3	ENST00000389212.7	c.1120G>C	p.Gly374Arg	missense_variant	12/29	2		ENSP00000373864.3
RAPGEF3	ENST00000549151.5	c.994G>C	p.Gly332Arg	missense_variant	11/28	5		ENSP00000448619.1
RAPGEF3	ENST00000548919.5	c.994G>C	p.Gly332Arg	missense_variant	11/27	2		ENSP00000448480.1
RAPGEF3	ENST00000395358.7	c.1120G>C	p.Gly374Arg	missense_variant	11/16	2		ENSP00000378764.3
RAPGEF3	ENST00000495465.6	n.*237G>C		non_coding_transcript_exon_variant	6/9	3		ENSP00000449818.1
RAPGEF3	ENST00000547856.5	n.*428G>C		non_coding_transcript_exon_variant	7/24	2		ENSP00000449905.1
RAPGEF3	ENST00000495465.6	n.*237G>C		3_prime_UTR_variant	6/9	3		ENSP00000449818.1
RAPGEF3	ENST00000547856.5	n.*428G>C		3_prime_UTR_variant	7/24	2		ENSP00000449905.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;.;T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.90	.;D;.;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.14	N;.;.;N;.;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.026	D;D;D;D;D;D
Sift4G	Benign	0.067	T;T;T;T;T;T
Polyphen		0.90	P;.;.;P;.;.
Vest4		0.28
MutPred		0.39		Gain of catalytic residue at P378 (P = 0);.;.;Gain of catalytic residue at P378 (P = 0);.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs12422983; hg19: chr12-48142636;