Genetic Variant RAPGEF6:p.Gly1249Asp (chr5-131433658-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016340.6(RAPGEF6):c.3746G>A(p.Gly1249Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000333 in 1,443,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

RAPGEF6
NM_016340.6 missense, splice_region

Scores

Splicing: ADA: 0.9987

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF6	NM_016340.6 link	c.3746G>A	p.Gly1249Asp	missense_variant, splice_region_variant	Exon 25 of 28	ENST00000509018.6	NP_057424.3	Q8TEU7-1
RAPGEF6	NM_001164386.2 link	c.3770G>A	p.Gly1257Asp	missense_variant, splice_region_variant	Exon 26 of 29		NP_001157858.1	Q8TEU7-4B2RTU6
RAPGEF6	NM_001164387.2 link	c.3785G>A	p.Gly1262Asp	missense_variant, splice_region_variant	Exon 27 of 29		NP_001157859.1	Q8TEU7-3
RAPGEF6	NM_001164388.2 link	c.3770G>A	p.Gly1257Asp	missense_variant, splice_region_variant	Exon 26 of 28		NP_001157860.1	Q8TEU7-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF6	ENST00000509018.6 link	c.3746G>A	p.Gly1249Asp	missense_variant, splice_region_variant	Exon 25 of 28	1	NM_016340.6	ENSP00000421684.1		Q8TEU7-1
ENSG00000273217	ENST00000514667.1 link	c.3896G>A	p.Gly1299Asp	missense_variant, splice_region_variant	Exon 26 of 29	2		ENSP00000426948.1		E9PCH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251068

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000333

AC:

AN:

1443496

Hom.:

Cov.:

AF XY:

0.0000348

AC XY:

AN XY:

719280

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:

0.0000438

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000244

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3770G>A (p.G1257D) alteration is located in exon 26 (coding exon 26) of the RAPGEF6 gene. This alteration results from a G to A substitution at nucleotide position 3770, causing the glycine (G) at amino acid position 1257 to be replaced by an aspartic acid (D). 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

0.32

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.47

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

M;.;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.7

D;.;D;.;D

REVEL

Benign

0.18

Sift

Uncertain

0.0010

D;.;D;.;D

Sift4G

Uncertain

0.057

T;T;T;T;T

Polyphen

0.026

B;D;.;.;.

Vest4

0.79

MutPred

0.22

.;.;.;.;Gain of relative solvent accessibility (P = 0.0082);

MVP

0.25

MPC

0.45, 0.25

ClinPred

0.91

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.89

SpliceAI score (max)

0.16

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