Variant chr12-47740173-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001098531.4(RAPGEF3):c.2341C>T(p.Arg781Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000128 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

RAPGEF3
NM_001098531.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.32

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4 linkuse as main transcript	c.2341C>T	p.Arg781Trp	missense_variant	23/28	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.2341C>T	p.Arg781Trp	missense_variant	23/28	2	NM_001098531.4	ENSP00000395708.2	O95398-1
RAPGEF3	ENST00000389212.7 linkuse as main transcript	c.2341C>T	p.Arg781Trp	missense_variant	24/29	2		ENSP00000373864.3	O95398-1
RAPGEF3	ENST00000549151.5 linkuse as main transcript	c.2215C>T	p.Arg739Trp	missense_variant	23/28	5		ENSP00000448619.1	O95398-3
RAPGEF3	ENST00000548919.5 linkuse as main transcript	c.2014C>T	p.Arg672Trp	missense_variant	22/27	2		ENSP00000448480.1	F8VRX1
RAPGEF3	ENST00000547856.5 linkuse as main transcript	n.*1649C>T		non_coding_transcript_exon_variant	19/24	2		ENSP00000449905.1	F8VVJ6
RAPGEF3	ENST00000547856.5 linkuse as main transcript	n.*1649C>T		3_prime_UTR_variant	19/24	2		ENSP00000449905.1	F8VVJ6

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000161

AC:

AN:

248942

Hom.:

AF XY:

0.000193

AC XY:

AN XY:

134984

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.000470

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000131

AC:

191

AN:

1461360

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000360

Gnomad4 FIN exome

AF:

0.000996

Gnomad4 NFE exome

AF:

0.0000800

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000105

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

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

May 07, 2024

The c.2341C>T (p.R781W) alteration is located in exon 23 (coding exon 23) of the RAPGEF3 gene. This alteration results from a C to T substitution at nucleotide position 2341, causing the arginine (R) at amino acid position 781 to be replaced by a tryptophan (W). 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

0.32

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;.;.;T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

.;D;.;D;D

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.65

D;D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.6

M;.;.;M;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.1

D;D;D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;.;D;.

Vest4

0.70

MVP

0.84

MPC

0.78

ClinPred

0.39

GERP RS

4.6

Varity_R

0.63

gMVP

0.63

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

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