Variant chr12-47746879-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001098531.4(RAPGEF3):c.1577A>G(p.Asn526Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,482 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: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RAPGEF3
NM_001098531.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.395

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049092054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPGEF3	NM_001098531.4 linkuse as main transcript	c.1577A>G	p.Asn526Ser	missense_variant	16/28	ENST00000449771.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPGEF3	ENST00000449771.7 linkuse as main transcript	c.1577A>G	p.Asn526Ser	missense_variant	16/28	2	NM_001098531.4	P4	O95398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448482

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720484

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Feb 28, 2023

The c.1577A>G (p.N526S) alteration is located in exon 16 (coding exon 16) of the RAPGEF3 gene. This alteration results from a A to G substitution at nucleotide position 1577, causing the asparagine (N) at amino acid position 526 to be replaced by a serine (S). 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

0.061

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.13

T;.;.;T;T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.27

M_CAP

Benign

0.016

MetaRNN

Benign

0.049

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

L;.;.;L;.;L

MutationTaster

Benign

0.78

D;D;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.83

N;N;N;N;N;N

REVEL

Benign

0.024

Sift

Benign

0.74

T;T;T;T;T;T

Sift4G

Benign

0.74

T;T;T;T;T;T

Polyphen

0.0

B;.;.;B;.;.

Vest4

0.13

MutPred

0.31

Gain of catalytic residue at N526 (P = 0.0013);.;.;Gain of catalytic residue at N526 (P = 0.0013);.;Gain of catalytic residue at N526 (P = 0.0013);

MVP

0.59

MPC

0.15

ClinPred

0.040

GERP RS

2.7

Varity_R

0.021

gMVP

0.081

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over