Genetic Variant RAPGEF3:p.Ser431Arg (chr12-47748103-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001098531.4(RAPGEF3):c.1293C>G(p.Ser431Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S431S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RAPGEF3
NM_001098531.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.983

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19538933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4 link	c.1293C>G	p.Ser431Arg	missense_variant	Exon 13 of 28	ENST00000449771.7	NP_001092001.2	Q99777

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAPGEF3	ENST00000449771.7 link	c.1293C>G	p.Ser431Arg	missense_variant	Exon 13 of 28	2	NM_001098531.4	ENSP00000395708.2	O95398-1
RAPGEF3	ENST00000389212.7 link	c.1293C>G	p.Ser431Arg	missense_variant	Exon 14 of 29	2		ENSP00000373864.3	O95398-1
RAPGEF3	ENST00000549151.5 link	c.1167C>G	p.Ser389Arg	missense_variant	Exon 13 of 28	5		ENSP00000448619.1	O95398-3
RAPGEF3	ENST00000548919.5 link	c.1167C>G	p.Ser389Arg	missense_variant	Exon 13 of 27	2		ENSP00000448480.1	F8VRX1
RAPGEF3	ENST00000395358.7 link	c.1293C>G	p.Ser431Arg	missense_variant	Exon 13 of 16	2		ENSP00000378764.3	O95398-2
RAPGEF3	ENST00000495465.6 link	n.*410C>G		non_coding_transcript_exon_variant	Exon 8 of 9	3		ENSP00000449818.1	H0YIP6
RAPGEF3	ENST00000547856.5 link	n.*601C>G		non_coding_transcript_exon_variant	Exon 9 of 24	2		ENSP00000449905.1	F8VVJ6
RAPGEF3	ENST00000495465.6 link	n.*410C>G		3_prime_UTR_variant	Exon 8 of 9	3		ENSP00000449818.1	H0YIP6
RAPGEF3	ENST00000547856.5 link	n.*601C>G		3_prime_UTR_variant	Exon 9 of 24	2		ENSP00000449905.1	F8VVJ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1436624

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712060

African (AFR)

AF:

0.00

AC:

AN:

33042

American (AMR)

AF:

0.00

AC:

AN:

40876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25636

East Asian (EAS)

AF:

0.00

AC:

AN:

38624

South Asian (SAS)

AF:

0.00

AC:

AN:

82642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099288

Other (OTH)

AF:

0.00

AC:

AN:

59510

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Benign

9.3

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.;.;T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.25

LIST_S2

Pathogenic

0.98

.;D;.;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.;.;L;.;L

PhyloP100

-0.98

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.3

N;N;N;N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.016

D;D;D;D;D;D

Sift4G

Uncertain

0.014

D;D;D;D;D;D

Polyphen

0.40

B;.;.;B;.;.

Vest4

0.57

MutPred

0.61

Gain of catalytic residue at F428 (P = 0);.;.;Gain of catalytic residue at F428 (P = 0);.;Gain of catalytic residue at F428 (P = 0);

MVP

0.21

MPC

0.48

ClinPred

0.59

GERP RS

-5.4

Varity_R

0.14

gMVP

0.78

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: -29

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over