Variant 20-63285711-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_018209.4(ARFGAP1):c.832A>G(p.Lys278Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00163 in 1,613,466 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts 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: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 7 hom. )

Consequence

ARFGAP1
NM_018209.4 missense, splice_region

Scores

Splicing: ADA: 0.09952

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.35

Variant links:

Genes affected

ARFGAP1 (HGNC:15852): (ADP ribosylation factor GTPase activating protein 1) The protein encoded by this gene is a GTPase-activating protein, which associates with the Golgi apparatus and which interacts with ADP-ribosylation factor 1. The encoded protein promotes hydrolysis of ADP-ribosylation factor 1-bound GTP and is required for the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. The activity of this protein is stimulated by phosphoinosides and inhibited by phosphatidylcholine. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ARFGAP1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09102154).

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGAP1	NM_018209.4 linkuse as main transcript	c.832A>G	p.Lys278Glu	missense_variant, splice_region_variant	11/13	ENST00000370283.9	NP_060679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGAP1	ENST00000370283.9 linkuse as main transcript	c.832A>G	p.Lys278Glu	missense_variant, splice_region_variant	11/13	1	NM_018209.4	ENSP00000359306	P1	Q8N6T3-1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

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:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000785

AC:

197

AN:

250894

Hom.:

AF XY:

0.000773

AC XY:

105

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00169

AC:

2468

AN:

1461120

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1179

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000473

Gnomad4 NFE exome

AF:

0.00212

Gnomad4 OTH exome

AF:

0.000977

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152346

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00210

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.000986

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000692

AC:

EpiCase

AF:

0.00185

EpiControl

AF:

0.00142

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

Nov 08, 2021

The c.862A>G (p.K288E) alteration is located in exon 12 (coding exon 11) of the ARFGAP1 gene. This alteration results from a A to G substitution at nucleotide position 862, causing the lysine (K) at amino acid position 288 to be replaced by a glutamic acid (E). 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

Pathogenic

0.58

BayesDel_addAF

Benign

-0.0048

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

.;.;T;.;T;T;.;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.58

T;D;D;T;D;D;T;D;T

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.090

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.031

MutationAssessor

Uncertain

2.3

.;.;M;.;.;.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.9

N;D;D;N;D;D;N;D;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.017

D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.11

T;D;D;T;D;D;D;T;T

Polyphen

0.82, 0.99

.;.;P;.;.;.;.;.;D

Vest4

0.88

MVP

0.73

MPC

0.19

ClinPred

0.052

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.65

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.10

dbscSNV1_RF

Benign

0.48

SpliceAI score (max)

0.15

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