rs143277734

Positions:

• chr20-48973148-C-A
• chr20-48973148-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The ENST00000371917.5(ARFGEF2):​c.1529C>A​(p.Ala510Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A510V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARFGEF2 ENST00000371917.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

Genes affected

ARFGEF2 (HGNC:15853): (ADP ribosylation factor guanine nucleotide exchange factor 2) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ARFGEF2. . Gene score misZ 2.5971 (greater than the threshold 3.09). Trascript score misZ 4.3519 (greater than threshold 3.09). GenCC has associacion of gene with periventricular nodular heterotopia, periventricular heterotopia with microcephaly, autosomal recessive.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.1529C>A	p.Ala510Asp	missense_variant	12/39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.1526C>A	p.Ala509Asp	missense_variant	12/39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.965C>A	p.Ala322Asp	missense_variant	10/37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.1529C>A	p.Ala510Asp	missense_variant	12/39	1	NM_006420.3	ENSP00000360985	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.71		Gain of sheet (P = 0.0827);
MVP		0.73
MPC		1.6
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143277734; hg19: chr20-47589685;