11-47168177-C-T

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.1016G>A(p.Arg339His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,238 control chromosomes in the GnomAD database, including 20 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. R339L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (13 hom., cov: 31)
  • Exomes 𝑓: 0.00075 (7 hom.)
• Consequence: ARFGAP2 NM_032389.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.30

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=0.008449376).
• BP6: Variant 11-47168177-C-T is Benign according to our data. Variant chr11-47168177-C-T is described in ClinVar as [Benign]. Clinvar id is 3055789.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0062 (944/152346) while in subpopulation AFR AF= 0.0217 (902/41580). AF 95% confidence interval is 0.0205. There are 13 homozygotes in gnomad4. There are 451 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARFGAP2	NM_032389.6	c.1016G>A	p.Arg339His	missense_variant	11/16	ENST00000524782.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARFGAP2	ENST00000524782.6	c.1016G>A	p.Arg339His	missense_variant	11/16	1	NM_032389.6	A1

Frequencies

GnomAD3 genomes AF: 0.00619 AC: 943 AN: 152228 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00169 AC: 426 AN: 251462 Hom.: 6 AF XY: 0.00100 AC XY: 136 AN XY: 135908

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000749 AC: 1095 AN: 1461892 Hom.: 7 Cov.: 33 AF XY: 0.000609 AC XY: 443 AN XY: 727248

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00620 AC: 944 AN: 152346 Hom.: 13 Cov.: 31 AF XY: 0.00605 AC XY: 451 AN XY: 74496

Gnomad4 AFR AF: 0.0217

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00204 Hom.: 1

Bravo AF: 0.00718

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00201 AC: 244

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jul 12, 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	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
MetaRNN	Benign	0.0084	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
REVEL	Benign	0.27
Sift4G	Benign	0.15	T;T;T;.
Polyphen		1.0	.;.;D;.
Vest4		0.74
MVP		0.41
MPC		0.89
ClinPred		0.038	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34662994; hg19: chr11-47189728;