rs2067309030

Variant names:

• chr20-63278982-C-T
• rs2067309030
• NM_018209.4:c.614C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018209.4(ARFGAP1):​c.614C>T​(p.Ser205Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ARFGAP1 NM_018209.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018209.4. 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
	ARFGAP1	NM_018209.4	MANE Select	c.614C>T	p.Ser205Phe	missense	Exon 7 of 13	NP_060679.1	Q8N6T3-1
	ARFGAP1	NM_175609.3		c.614C>T	p.Ser205Phe	missense	Exon 7 of 14	NP_783202.1	Q8N6T3-2
	ARFGAP1	NM_001281482.2		c.614C>T	p.Ser205Phe	missense	Exon 7 of 14	NP_001268411.1	Q8N6T3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGAP1	ENST00000370283.9	TSL:1 MANE Select	c.614C>T	p.Ser205Phe	missense	Exon 7 of 13	ENSP00000359306.4	Q8N6T3-1
	ARFGAP1	ENST00000353546.7	TSL:1	c.614C>T	p.Ser205Phe	missense	Exon 7 of 14	ENSP00000314615.3	Q8N6T3-2
	ARFGAP1	ENST00000370275.8	TSL:1	c.614C>T	p.Ser205Phe	missense	Exon 7 of 14	ENSP00000359298.4	Q8N6T3-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111988

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.96	D
Vest4		0.87
MutPred		0.52		Loss of disorder (P = 0.0091)
MVP		0.81
MPC		0.60
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.83
Mutation Taster		=23/77	disease causing

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: rs2067309030; hg19: chr20-61910334;