chr12-48939078-T-C

Position:

• chr12-48939078-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001659.3(ARF3):​c.415A>G​(p.Ile139Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARF3 NM_001659.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25

Genes affected

ARF3 (HGNC:654): (ADP ribosylation factor 3) ADP-ribosylation factor 3 (ARF3) is a member of the human ARF gene family. These genes encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking and as activators of phospholipase D. The gene products include 6 ARF proteins and 11 ARF-like proteins and constitute one family of the RAS superfamily. The ARF proteins are categorized as class I (ARF1, ARF2,and ARF3), class II (ARF4 and ARF5) and class III (ARF6) and members of each class share a common gene organization. [provided by RefSeq, Oct 2022]

ENSG00000272822 (HGNC:):

FKBP11 (HGNC:18624): (FKBP prolyl isomerase 11) FKBP11 belongs to the FKBP family of peptidyl-prolyl cis/trans isomerases, which catalyze the folding of proline-containing polypeptides. The peptidyl-prolyl isomerase activity of FKBP proteins is inhibited by the immunosuppressant compounds FK506 and rapamycin (Rulten et al., 2006 [PubMed 16596453]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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), ARF3. . Gene score misZ 2.8247 (greater than the threshold 3.09). Trascript score misZ 3.6833 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30990505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARF3	NM_001659.3	c.415A>G	p.Ile139Val	missense_variant	5/5	ENST00000256682.9	NP_001650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARF3	ENST00000256682.9	c.415A>G	p.Ile139Val	missense_variant	5/5	1	NM_001659.3	ENSP00000256682.4
ENSG00000272822	ENST00000398092.4	c.384+577A>G		intron_variant		3		ENSP00000438507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.072
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	.;N;.;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.62	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.0	.;B;.;B
Vest4		0.19, 0.32, 0.20
MutPred		0.58		.;Gain of catalytic residue at N135 (P = 0.0438);.;Gain of catalytic residue at N135 (P = 0.0438);
MVP		0.26
MPC		1.1
ClinPred		0.81	D
GERP RS		4.3
Varity_R		0.11
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1940206563; hg19: chr12-49332861;