Variant chr17-40193688-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_016339.6(RAPGEFL1):c.1889A>G(p.Asn630Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

RAPGEFL1
NM_016339.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

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:

RAPGEFL1 (HGNC:):

RAPGEFL1 links:

Genome browser will be placed here

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=0.01443705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEFL1	NM_016339.6 linkuse as main transcript	c.1889A>G	p.Asn630Ser	missense_variant	15/15	ENST00000620260.6	NP_057423.2	Q9UHV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RAPGEFL1	ENST00000620260.6 linkuse as main transcript	c.1889A>G	p.Asn630Ser	missense_variant	15/15	1	NM_016339.6	ENSP00000479735.1	A0A087WVW6
RAPGEFL1	ENST00000456989.6 linkuse as main transcript	c.1436A>G	p.Asn479Ser	missense_variant	15/15	1		ENSP00000394530.2	Q9UHV5-3
RAPGEFL1	ENST00000544503.5 linkuse as main transcript	c.1418A>G	p.Asn473Ser	missense_variant	15/15	2		ENSP00000438631.1	F5H2D5
RAPGEFL1	ENST00000264644.10 linkuse as main transcript	c.1271A>G	p.Asn424Ser	missense_variant	15/15	5		ENSP00000264644.5	Q9UHV5-2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251466

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000582

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Aug 12, 2021

The c.1271A>G (p.N424S) alteration is located in exon 15 (coding exon 13) of the RAPGEFL1 gene. This alteration results from a A to G substitution at nucleotide position 1271, causing the asparagine (N) at amino acid position 424 to be replaced by a serine (S). 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

0.060

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.017

.;T;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.28

T;T;T;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.85

N;N;.;.

REVEL

Benign

0.086

Sift

Benign

0.55

T;T;.;.

Sift4G

Benign

0.82

T;T;T;T

Vest4

0.11

MutPred

0.24

.;.;.;Gain of disorder (P = 0.0463);

MVP

0.082

ClinPred

0.056

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.088

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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