11-47166876-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R406Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0055 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (9 hom.)
• Consequence: ARFGAP2 NM_032389.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.94

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]

ACMG classification

Verdict is Benign. Variant got -14 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 criteria_provided_single_submitter, 1 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 GnomAd at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARFGAP2	NM_032389.6	c.1216C>T	p.Arg406Trp	missense_variant	13/16	ENST00000524782.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARFGAP2	ENST00000524782.6	c.1216C>T	p.Arg406Trp	missense_variant	13/16	1	NM_032389.6	A1

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 839 AN: 152164 Hom.: 12 Cov.: 33

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.: 8 AF XY: 0.00182 AC XY: 247 AN XY: 135592

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.: 9 Cov.: 34 AF XY: 0.000860 AC XY: 625 AN XY: 726964

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.: 12 Cov.: 33 AF XY: 0.00529 AC XY: 394 AN XY: 74456

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.: 2

Bravo AF: 0.00693

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0189 AC: 83

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00262 AC: 318

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ARFGAP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2019

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	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
MetaRNN	Benign	0.0066	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
REVEL	Benign	0.24
Sift4G	Uncertain	0.012	D;D;D;D;.
Polyphen		1.0	.;.;D;.;.
Vest4		0.66
MVP		0.30
MPC		0.86
ClinPred		0.066	T
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

Other links and lift over

dbSNP: rs35950498; hg19: chr11-47188427;