Variant chr12-47740778-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001098531.4(RAPGEF3):c.2095G>A(p.Val699Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RAPGEF3
NM_001098531.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

Variant links:

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 links:

RAPGEF3 (HGNC:):

RAPGEF3 links:

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ACMG classification

Classification made for transcript

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=0.112588525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4 linkuse as main transcript	c.2095G>A	p.Val699Ile	missense_variant	21/28	ENST00000449771.7	NP_001092001.2	Q99777

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RAPGEF3	ENST00000449771.7 linkuse as main transcript	c.2095G>A	p.Val699Ile	missense_variant	21/28	2	NM_001098531.4	ENSP00000395708.2	O95398-1
RAPGEF3	ENST00000389212.7 linkuse as main transcript	c.2095G>A	p.Val699Ile	missense_variant	22/29	2		ENSP00000373864.3	O95398-1
RAPGEF3	ENST00000549151.5 linkuse as main transcript	c.1969G>A	p.Val657Ile	missense_variant	21/28	5		ENSP00000448619.1	O95398-3
RAPGEF3	ENST00000548919.5 linkuse as main transcript	c.1822G>A	p.Val608Ile	missense_variant	20/27	2		ENSP00000448480.1	F8VRX1
RAPGEF3	ENST00000547856.5 linkuse as main transcript	n.*1403G>A		non_coding_transcript_exon_variant	17/24	2		ENSP00000449905.1	F8VVJ6
RAPGEF3	ENST00000547856.5 linkuse as main transcript	n.*1403G>A		3_prime_UTR_variant	17/24	2		ENSP00000449905.1	F8VVJ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249636

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.2095G>A (p.V699I) alteration is located in exon 21 (coding exon 21) of the RAPGEF3 gene. This alteration results from a G to A substitution at nucleotide position 2095, causing the valine (V) at amino acid position 699 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.073

T;.;.;T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.72

.;T;.;T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.;.;N;.

MutationTaster

Benign

0.86

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.060

N;N;N;N;N

REVEL

Benign

0.032

Sift

Benign

0.68

T;T;T;T;T

Sift4G

Benign

0.35

T;T;T;T;T

Polyphen

0.18

B;.;.;B;.

Vest4

0.17

MutPred

0.44

Gain of catalytic residue at R697 (P = 0.0155);.;.;Gain of catalytic residue at R697 (P = 0.0155);.;

MVP

0.56

MPC

0.16

ClinPred

0.22

GERP RS

2.9

Varity_R

0.022

gMVP

0.067

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over