12-47738225-C-T

Position:

chr12-47738225-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001098531.4(RAPGEF3):c.2549G>A(p.Arg850Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,498 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RAPGEF3
NM_001098531.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

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:

RPAP3-DT (HGNC:55477): (RPAP3 divergent transcript)

RPAP3-DT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.42155412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4 link	c.2549G>A	p.Arg850Gln	missense_variant	26/28	ENST00000449771.7	NP_001092001.2	Q99777

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RAPGEF3	ENST00000449771.7 link	c.2549G>A	p.Arg850Gln	missense_variant	26/28	2	NM_001098531.4	ENSP00000395708.2	O95398-1
RAPGEF3	ENST00000389212.7 link	c.2549G>A	p.Arg850Gln	missense_variant	27/29	2		ENSP00000373864.3	O95398-1
RAPGEF3	ENST00000549151.5 link	c.2423G>A	p.Arg808Gln	missense_variant	26/28	5		ENSP00000448619.1	O95398-3
RAPGEF3	ENST00000548919.5 link	c.2222G>A	p.Arg741Gln	missense_variant	25/27	2		ENSP00000448480.1	F8VRX1
RAPGEF3	ENST00000547856.5 link	n.*1857G>A		non_coding_transcript_exon_variant	22/24	2		ENSP00000449905.1	F8VVJ6
RAPGEF3	ENST00000547856.5 link	n.*1857G>A		3_prime_UTR_variant	22/24	2		ENSP00000449905.1	F8VVJ6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250608

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000930

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461284

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

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

Oct 11, 2024

The c.2549G>A (p.R850Q) alteration is located in exon 26 (coding exon 26) of the RAPGEF3 gene. This alteration results from a G to A substitution at nucleotide position 2549, causing the arginine (R) at amino acid position 850 to be replaced by a glutamine (Q). 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

0.087

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;.;D;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.90

.;D;.;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.42

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;.;L;.

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.8

D;D;D;D;D

REVEL

Benign

0.086

Sift

Benign

0.043

D;D;D;D;D

Sift4G

Uncertain

0.043

D;D;D;D;D

Polyphen

0.021

B;.;.;B;.

Vest4

0.57

MutPred

0.48

Gain of catalytic residue at M851 (P = 0);.;.;Gain of catalytic residue at M851 (P = 0);.;

MVP

0.61

MPC

0.27

ClinPred

0.80

GERP RS

5.0

Varity_R

0.16

gMVP

0.43

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