Variant 5-131433542-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016340.6(RAPGEF6):c.3862C>G(p.Leu1288Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,144 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: 32)

Consequence

RAPGEF6
NM_016340.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.45

Variant links:

Genes affected

RAPGEF6 (HGNC:20655): (Rap guanine nucleotide exchange factor 6) Enables several functions, including GTP-dependent protein binding activity; guanyl-nucleotide exchange factor activity; and phosphatidic acid binding activity. Involved in microvillus assembly; positive regulation of GTPase activity; and protein localization to plasma membrane. Located in several cellular components, including apical plasma membrane; centrosome; and endocytic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

RAPGEF6 links:

ENSG00000273217 (HGNC:):

ENSG00000273217 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13926634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF6	NM_016340.6 linkuse as main transcript	c.3862C>G	p.Leu1288Val	missense_variant	25/28	ENST00000509018.6	NP_057424.3	Q8TEU7-1
RAPGEF6	NM_001164386.2 linkuse as main transcript	c.3886C>G	p.Leu1296Val	missense_variant	26/29		NP_001157858.1	Q8TEU7-4B2RTU6
RAPGEF6	NM_001164387.2 linkuse as main transcript	c.3901C>G	p.Leu1301Val	missense_variant	27/29		NP_001157859.1	Q8TEU7-3
RAPGEF6	NM_001164388.2 linkuse as main transcript	c.3886C>G	p.Leu1296Val	missense_variant	26/28		NP_001157860.1	Q8TEU7-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF6	ENST00000509018.6 linkuse as main transcript	c.3862C>G	p.Leu1288Val	missense_variant	25/28	1	NM_016340.6	ENSP00000421684.1		Q8TEU7-1
ENSG00000273217	ENST00000514667.1 linkuse as main transcript	c.4012C>G	p.Leu1338Val	missense_variant	26/29	2		ENSP00000426948.1		E9PCH4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

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

Sep 27, 2021

The c.3886C>G (p.L1296V) alteration is located in exon 26 (coding exon 26) of the RAPGEF6 gene. This alteration results from a C to G substitution at nucleotide position 3886, causing the leucine (L) at amino acid position 1296 to be replaced by a valine (V). 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

0.067

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.;.;.;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Benign

0.0064

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;.;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.38

N;.;N;.;N

REVEL

Benign

0.065

Sift

Benign

0.044

D;.;D;.;D

Sift4G

Benign

0.56

T;T;T;T;T

Polyphen

0.28

B;P;.;.;.

Vest4

0.069

MutPred

0.13

.;.;.;.;Loss of helix (P = 0.0558);

MVP

0.33

MPC

0.23, 0.16

ClinPred

0.62

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.23

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