Variant 7-22145048-C-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_012294.5(RAPGEF5):c.2182G>A(p.Ala728Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAPGEF5
NM_012294.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.68

Variant links:

Genes affected

RAPGEF5 (HGNC:16862): (Rap guanine nucleotide exchange factor 5) Members of the RAS (see HRAS; MIM 190020) subfamily of GTPases function in signal transduction as GTP/GDP-regulated switches that cycle between inactive GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs), such as RAPGEF5, serve as RAS activators by promoting acquisition of GTP to maintain the active GTP-bound state and are the key link between cell surface receptors and RAS activation (Rebhun et al., 2000 [PubMed 10934204]).[supplied by OMIM, Mar 2008]

RAPGEF5 links:

Genome browser will be placed here

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
RAPGEF5	NM_012294.5 link	c.2182G>A	p.Ala728Thr	missense_variant	20/26	ENST00000665637.1	NP_036426.4	Q92565A8MQ07Q5JPD2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RAPGEF5	ENST00000665637.1 link	c.2182G>A	p.Ala728Thr	missense_variant	20/26		NM_012294.5	ENSP00000499535.1	A0A590UJR0
RAPGEF5	ENST00000401957.6 link	c.1273G>A	p.Ala425Thr	missense_variant	10/16	1		ENSP00000384044.1	Q92565-1
RAPGEF5	ENST00000344041.10 link	c.1723G>A	p.Ala575Thr	missense_variant	20/26	5		ENSP00000343656.6	A8MQ07
RAPGEF5	ENST00000468825.1 link	n.219G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247772

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134438

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

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:

6.85e-7

AC:

AN:

1460316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

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

Jun 29, 2023

The c.1723G>A (p.A575T) alteration is located in exon 20 (coding exon 17) of the RAPGEF5 gene. This alteration results from a G to A substitution at nucleotide position 1723, causing the alanine (A) at amino acid position 575 to be replaced by a threonine (T). 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

Uncertain

0.34

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;.;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

2.0

M;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.7

D;D;.

REVEL

Uncertain

0.30

Sift

Benign

0.032

D;D;.

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.97

D;D;.

Vest4

0.41

MutPred

0.50

.;Loss of MoRF binding (P = 0.1398);.;

MVP

0.19

MPC

0.62

ClinPred

0.95

GERP RS

6.2

Varity_R

0.52

gMVP

0.14

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