Genetic Variant RAPGEFL1:p.Gly260Ala (chr17-40184624-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016339.6(RAPGEFL1):c.779G>C(p.Gly260Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000761 in 1,590,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

RAPGEFL1
NM_016339.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.81

Variant links:

Genes affected

RAPGEFL1 (HGNC:17428): (Rap guanine nucleotide exchange factor like 1) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in G protein-coupled receptor signaling pathway and nervous system development. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

RAPGEFL1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0076688826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEFL1	NM_016339.6 link	c.779G>C	p.Gly260Ala	missense_variant	Exon 4 of 15	ENST00000620260.6	NP_057423.2	Q9UHV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAPGEFL1	ENST00000620260.6 link	c.779G>C	p.Gly260Ala	missense_variant	Exon 4 of 15	1	NM_016339.6	ENSP00000479735.1	A0A087WVW6
RAPGEFL1	ENST00000456989.6 link	c.326G>C	p.Gly109Ala	missense_variant	Exon 4 of 15	1		ENSP00000394530.2	Q9UHV5-3
RAPGEFL1	ENST00000544503.5 link	c.308G>C	p.Gly103Ala	missense_variant	Exon 4 of 15	2		ENSP00000438631.1	F5H2D5
RAPGEFL1	ENST00000264644.10 link	c.161G>C	p.Gly54Ala	missense_variant	Exon 4 of 15	5		ENSP00000264644.5	Q9UHV5-2
RAPGEFL1	ENST00000543876.5 link	c.161G>C	p.Gly54Ala	missense_variant	Exon 4 of 6	4		ENSP00000440226.1	F5GYJ3
RAPGEFL1	ENST00000538981.1 link	c.161G>C	p.Gly54Ala	missense_variant	Exon 3 of 4	2		ENSP00000441059.1	F5GXC6

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000478

GnomAD3 exomes

AF:

0.000104

AC:

AN:

229768

Hom.:

AF XY:

0.0000402

AC XY:

AN XY:

124366

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.0000612

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:

0.00000977

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1438220

Hom.:

Cov.:

AF XY:

0.0000266

AC XY:

AN XY:

715068

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.0000232

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:

0.00000548

Gnomad4 OTH exome

AF:

0.0000840

GnomAD4 genome

AF:

0.000368

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.000262

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:

0.000473

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.000472

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161G>C (p.G54A) alteration is located in exon 4 (coding exon 2) of the RAPGEFL1 gene. This alteration results from a G to C substitution at nucleotide position 161, causing the glycine (G) at amino acid position 54 to be replaced by an alanine (A). 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

0.080

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0019

.;T;T;.;T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.84

T;T;T;T;T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.0077

T;T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.45

PROVEAN

Benign

1.1

N;N;N;.;.;N

REVEL

Benign

0.057

Sift

Benign

1.0

T;T;T;.;.;T

Sift4G

Benign

0.75

T;T;T;T;T;T

Vest4

0.20

MVP

0.093

ClinPred

0.014

GERP RS

4.1

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