Variant chr12-47740160-G-T 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.2354C>A(p.Ser785Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,613,388 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

RAPGEF3
NM_001098531.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.80

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.2354C>A	p.Ser785Tyr	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.2354C>A	p.Ser785Tyr	missense_variant	23/28	2	NM_001098531.4	ENSP00000395708.2	O95398-1
RAPGEF3	ENST00000389212.7 linkuse as main transcript	c.2354C>A	p.Ser785Tyr	missense_variant	24/29	2		ENSP00000373864.3	O95398-1
RAPGEF3	ENST00000549151.5 linkuse as main transcript	c.2228C>A	p.Ser743Tyr	missense_variant	23/28	5		ENSP00000448619.1	O95398-3
RAPGEF3	ENST00000548919.5 linkuse as main transcript	c.2027C>A	p.Ser676Tyr	missense_variant	22/27	2		ENSP00000448480.1	F8VRX1
RAPGEF3	ENST00000547856.5 linkuse as main transcript	n.*1662C>A		non_coding_transcript_exon_variant	19/24	2		ENSP00000449905.1	F8VVJ6
RAPGEF3	ENST00000547856.5 linkuse as main transcript	n.*1662C>A		3_prime_UTR_variant	19/24	2		ENSP00000449905.1	F8VVJ6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248670

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000165

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461208

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726908

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

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

Jul 06, 2024

The c.2354C>A (p.S785Y) alteration is located in exon 23 (coding exon 23) of the RAPGEF3 gene. This alteration results from a C to A substitution at nucleotide position 2354, causing the serine (S) at amino acid position 785 to be replaced by a tyrosine (Y). 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

0.21

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;.;.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.84

.;T;.;T;D

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.50

T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.0

M;.;.;M;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.1

D;D;D;D;D

REVEL

Benign

0.12

Sift

Uncertain

0.012

D;D;D;D;D

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.29

B;.;.;B;.

Vest4

0.52

MVP

0.74

MPC

0.65

ClinPred

0.91

GERP RS

4.6

Varity_R

0.30

gMVP

0.44

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