22-42808879-C-T

Variant names:

• chr22-42808879-C-T
• rs138028492
• NM_014570.5:c.1208G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014570.5(ARFGAP3):​c.1208G>A​(p.Arg403His) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 1,608,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R403P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ARFGAP3 NM_014570.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.24
• Publications: 1 publications found

Genes affected

ARFGAP3 (HGNC:661): (ADP ribosylation factor GTPase activating protein 3) The protein encoded by this gene is a GTPase-activating protein (GAP) that associates with the Golgi apparatus and regulates the early secretory pathway of proteins. The encoded protein promotes hydrolysis of ADP-ribosylation factor 1 (ARF1)-bound GTP, which is required for the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is a prerequisite for the fusion of these vesicles with target compartments. The activity of this protein is sensitive to phospholipids. Multiple transcript variants encoding different isoforms have been found for this gene. This gene was originally known as ARFGAP1, but that is now the name of a related but different gene. [provided by RefSeq, Nov 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37488413).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014570.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGAP3	NM_014570.5	MANE Select	c.1208G>A	p.Arg403His	missense	Exon 13 of 16	NP_055385.3
	ARFGAP3	NM_001142293.2		c.1076G>A	p.Arg359His	missense	Exon 12 of 15	NP_001135765.1	Q9NP61-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGAP3	ENST00000263245.10	TSL:1 MANE Select	c.1208G>A	p.Arg403His	missense	Exon 13 of 16	ENSP00000263245.5	Q9NP61-1
	ARFGAP3	ENST00000437119.6	TSL:1	c.1076G>A	p.Arg359His	missense	Exon 12 of 15	ENSP00000388791.2	Q9NP61-2
	ARFGAP3	ENST00000938504.1		c.1148G>A	p.Arg383His	missense	Exon 12 of 15	ENSP00000608563.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000402 AC: 10 AN: 248780 AF XY: 0.0000372

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1456578 Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13 AN XY: 724370

African (AFR) AF: 0.0000899 AC: 3 AN: 33386

American (AMR) AF: 0.000113 AC: 5 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39562

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1108920

Other (OTH) AF: 0.0000332 AC: 2 AN: 60154

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74306

African (AFR) AF: 0.0000483 AC: 2 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.073	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.2
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.28		Gain of methylation at K405 (P = 0.094)
MVP		0.54
MPC		0.12
ClinPred		0.90	D
GERP RS		4.8
Varity_R		0.34
gMVP		0.41
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs138028492; hg19: chr22-43204885;