20-63276107-G-C

Variant names:

• chr20-63276107-G-C
• NM_018209.4:c.77G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018209.4(ARFGAP1):​c.77G>C​(p.Gly26Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,746 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARFGAP1 NM_018209.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.63

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGAP1	NM_018209.4	c.77G>C	p.Gly26Ala	missense_variant	Exon 3 of 13	ENST00000370283.9	NP_060679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGAP1	ENST00000370283.9	c.77G>C	p.Gly26Ala	missense_variant	Exon 3 of 13	1	NM_018209.4	ENSP00000359306.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461746 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.77G>C (p.G26A) alteration is located in exon 3 (coding exon 2) of the ARFGAP1 gene. This alteration results from a G to C substitution at nucleotide position 77, causing the glycine (G) at amino acid position 26 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.;.;.;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.8	M;.;M;M;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.1	D;D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;T;T;D;D;T
Sift4G	Uncertain	0.025	D;T;T;D;T;T
Polyphen		0.98	D;.;.;D;.;.
Vest4		0.73
MutPred		0.69		Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);
MVP		0.67
MPC		0.56
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.86
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-61907459;