12-47741012-G-A

Position:

chr12-47741012-G-A

Variant summary

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

The NM_001098531.4(RAPGEF3):c.1952C>T(p.Thr651Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,612,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RAPGEF3
NM_001098531.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.127

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:

Genome browser will be placed here

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=0.02653566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4 linkuse as main transcript	c.1952C>T	p.Thr651Ile	missense_variant	20/28	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.1952C>T	p.Thr651Ile	missense_variant	20/28	2	NM_001098531.4	ENSP00000395708.2	O95398-1
RAPGEF3	ENST00000389212.7 linkuse as main transcript	c.1952C>T	p.Thr651Ile	missense_variant	21/29	2		ENSP00000373864.3	O95398-1
RAPGEF3	ENST00000549151.5 linkuse as main transcript	c.1826C>T	p.Thr609Ile	missense_variant	20/28	5		ENSP00000448619.1	O95398-3
RAPGEF3	ENST00000548919.5 linkuse as main transcript	c.1679C>T	p.Thr560Ile	missense_variant	19/27	2		ENSP00000448480.1	F8VRX1
RAPGEF3	ENST00000547856.5 linkuse as main transcript	n.*1260C>T		non_coding_transcript_exon_variant	16/24	2		ENSP00000449905.1	F8VVJ6
RAPGEF3	ENST00000547856.5 linkuse as main transcript	n.*1260C>T		3_prime_UTR_variant	16/24	2		ENSP00000449905.1	F8VVJ6

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000738

AC:

AN:

243816

Hom.:

AF XY:

0.0000528

AC XY:

AN XY:

132552

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.0000397

AC:

AN:

1460526

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726448

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000354

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000279

Hom.:

Bravo

AF:

0.000438

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000989

AC:

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

Dec 04, 2024

The c.1952C>T (p.T651I) alteration is located in exon 20 (coding exon 20) of the RAPGEF3 gene. This alteration results from a C to T substitution at nucleotide position 1952, causing the threonine (T) at amino acid position 651 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

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;.;D;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.85

.;T;.;T;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.027

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;.;.;M;.

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.6

D;D;D;D;D

REVEL

Benign

0.048

Sift

Uncertain

0.015

D;D;D;D;D

Sift4G

Benign

0.13

T;T;T;T;T

Polyphen

0.90

P;.;.;P;.

Vest4

0.17

MVP

0.58

MPC

0.22

ClinPred

0.13

GERP RS

1.9

Varity_R

0.17

gMVP

0.30

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