Genetic Variant ARFGAP2:p.Arg406Trp (chr11-47166876-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032389.6(ARFGAP2):c.1216C>T(p.Arg406Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,546 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0055 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 9 hom. )

Consequence

ARFGAP2
NM_032389.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.94

Variant links:

Genes affected

ARFGAP2 (HGNC:13504): (ADP ribosylation factor GTPase activating protein 2) Predicted to enable GTPase activator activity. Predicted to be involved in COPI coating of Golgi vesicle. Located in Golgi apparatus; cytosol; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARFGAP2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065661967).

BP6

Variant 11-47166876-G-A is Benign according to our data. Variant chr11-47166876-G-A is described in ClinVar as [Benign]. Clinvar id is 3045169.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0055 (838/152282) while in subpopulation AFR AF= 0.0176 (733/41550). AF 95% confidence interval is 0.0166. There are 12 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGAP2	NM_032389.6 link	c.1216C>T	p.Arg406Trp	missense_variant	Exon 13 of 16	ENST00000524782.6	NP_115765.2	Q8N6H7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGAP2	ENST00000524782.6 link	c.1216C>T	p.Arg406Trp	missense_variant	Exon 13 of 16	1	NM_032389.6	ENSP00000434442.1		Q8N6H7-1

Frequencies

GnomAD3 genomes

AF:

0.00551

AC:

839

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0177

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00227

AC:

568

AN:

250754

Hom.:

AF XY:

0.00182

AC XY:

247

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.0184

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00856

Gnomad EAS exome

AF:

0.00441

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0000470

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000977

AC:

1428

AN:

1461264

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

625

AN XY:

726964

show subpopulations

Gnomad4 AFR exome

AF:

0.0184

Gnomad4 AMR exome

AF:

0.00161

Gnomad4 ASJ exome

AF:

0.00796

Gnomad4 EAS exome

AF:

0.00219

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000248

Gnomad4 OTH exome

AF:

0.00253

GnomAD4 genome

AF:

0.00550

AC:

838

AN:

152282

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

394

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0176

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00693

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0189

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00262

AC:

318

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ARFGAP2-related disorder

Benign:1

Oct 04, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;T;T;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D;D;D

MetaRNN

Benign

0.0066

T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Pathogenic

3.1

.;.;M;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.5

.;.;D;N;D

REVEL

Benign

0.24

Sift

Uncertain

0.0030

.;.;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D;.

Polyphen

1.0

.;.;D;.;.

Vest4

0.66

MVP

0.30

MPC

0.86

ClinPred

0.066

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

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