Genetic Variant NM_016339.6:c.779G>C (chr17-40184624-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_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. 14/20 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

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016339.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAPGEFL1	NM_016339.6	MANE Select	c.779G>C	p.Gly260Ala	missense	Exon 4 of 15	NP_057423.2	A0A087WVW6
RAPGEFL1	NM_001303533.2		c.326G>C	p.Gly109Ala	missense	Exon 4 of 15	NP_001290462.1	Q9UHV5-3
RAPGEFL1	NM_001303534.3		c.308G>C	p.Gly103Ala	missense	Exon 4 of 15	NP_001290463.1	F5H2D5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAPGEFL1	ENST00000620260.6	TSL:1 MANE Select	c.779G>C	p.Gly260Ala	missense	Exon 4 of 15	ENSP00000479735.1	A0A087WVW6
RAPGEFL1	ENST00000456989.6	TSL:1	c.326G>C	p.Gly109Ala	missense	Exon 4 of 15	ENSP00000394530.2	Q9UHV5-3
RAPGEFL1	ENST00000544503.5	TSL:2	c.308G>C	p.Gly103Ala	missense	Exon 4 of 15	ENSP00000438631.1	F5H2D5

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

GnomAD2 exomes

AF:

0.000104

AC:

AN:

229768

AF XY:

0.0000402

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 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

African (AFR)

AF:

0.00161

AC:

AN:

32998

American (AMR)

AF:

0.0000232

AC:

AN:

43150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25706

East Asian (EAS)

AF:

0.00

AC:

AN:

39340

South Asian (SAS)

AF:

0.00

AC:

AN:

84036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00000548

AC:

AN:

1095174

Other (OTH)

AF:

0.0000840

AC:

AN:

59514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000368

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41508

American (AMR)

AF:

0.000262

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0019

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.84

M_CAP

Benign

0.0046

MetaRNN

Benign

0.0077

MetaSVM

Benign

-1.0

PhyloP100

3.8

PrimateAI

Benign

0.45

PROVEAN

Benign

1.1

REVEL

Benign

0.057

Sift

Benign

1.0

Sift4G

Benign

0.75

Vest4

0.20

MVP

0.093

ClinPred

0.014

GERP RS

4.1

gMVP

0.14

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over