Genetic Variant NM_016339.6:c.1210C>G (chr17-40190529-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_016339.6(RAPGEFL1):c.1210C>G(p.Leu404Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RAPGEFL1
NM_016339.6 missense, splice_region

Scores

Splicing: ADA: 0.001496

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01

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:

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 rank	MANE	Protein	UniProt
RAPGEFL1	NM_016339.6 link	c.1210C>G	p.Leu404Val	missense_variant, splice_region_variant	Exon 7 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.1210C>G	p.Leu404Val	missense_variant, splice_region_variant	Exon 7 of 15	1	NM_016339.6	ENSP00000479735.1	A0A087WVW6
RAPGEFL1	ENST00000456989.6 link	c.757C>G	p.Leu253Val	missense_variant, splice_region_variant	Exon 7 of 15	1		ENSP00000394530.2	Q9UHV5-3
RAPGEFL1	ENST00000544503.5 link	c.739C>G	p.Leu247Val	missense_variant, splice_region_variant	Exon 7 of 15	2		ENSP00000438631.1	F5H2D5
RAPGEFL1	ENST00000264644.10 link	c.592C>G	p.Leu198Val	missense_variant, splice_region_variant	Exon 7 of 15	5		ENSP00000264644.5	Q9UHV5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251480

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727230

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.592C>G (p.L198V) alteration is located in exon 7 (coding exon 5) of the RAPGEFL1 gene. This alteration results from a C to G substitution at nucleotide position 592, causing the leucine (L) at amino acid position 198 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

0.29

BayesDel_addAF

Benign

-0.0023

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.072

.;T;.;T

Eigen

Benign

0.082

Eigen_PC

Benign

-0.016

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Benign

-0.59

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.5

D;D;.;.

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Benign

0.12

T;T;T;D

Vest4

0.61

MutPred

0.59

.;.;.;Gain of phosphorylation at Y401 (P = 0.1326);

MVP

0.068

ClinPred

0.98

GERP RS

3.2

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0015

dbscSNV1_RF

Benign

0.10

SpliceAI score (max)

0.020

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