5-131429184-T-C

Position:

• chr5-131429184-T-C

Variant summary

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

The NM_016340.6(RAPGEF6):​c.4498A>G​(p.Arg1500Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAPGEF6 NM_016340.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.42

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]

ENSG00000273217 (HGNC:):

ACMG classification

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
RAPGEF6	NM_016340.6	c.4498A>G	p.Arg1500Gly	missense_variant	27/28	ENST00000509018.6	NP_057424.3
RAPGEF6	NM_001164386.2	c.4522A>G	p.Arg1508Gly	missense_variant	28/29		NP_001157858.1
RAPGEF6	NM_001164387.2	c.4504+1675A>G		intron_variant			NP_001157859.1
RAPGEF6	NM_001164388.2	c.4489+1675A>G		intron_variant			NP_001157860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF6	ENST00000509018.6	c.4498A>G	p.Arg1500Gly	missense_variant	27/28	1	NM_016340.6	ENSP00000421684.1
ENSG00000273217	ENST00000514667.1	c.4648A>G	p.Arg1550Gly	missense_variant	28/29	2		ENSP00000426948.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

The c.4522A>G (p.R1508G) alteration is located in exon 28 (coding exon 28) of the RAPGEF6 gene. This alteration results from a A to G substitution at nucleotide position 4522, causing the arginine (R) at amino acid position 1508 to be replaced by a glycine (G). 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	0.39
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.046	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.78
MutPred		0.30		.;.;Gain of relative solvent accessibility (P = 0.0507);
MVP		0.43
MPC		0.79, 0.74
ClinPred		0.92	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.81

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

Other links and lift over

dbSNP: rs1751550454; hg19: chr5-130764877;