chr12-48940957-G-A

Position:

• chr12-48940957-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001659.3(ARF3):​c.139C>T​(p.Pro47Ser) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARF3 NM_001659.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 10.0

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 12-48940957-G-A is Pathogenic according to our data. Variant chr12-48940957-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1697210.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARF3	NM_001659.3	c.139C>T	p.Pro47Ser	missense_variant	2/5	ENST00000256682.9	NP_001650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARF3	ENST00000256682.9	c.139C>T	p.Pro47Ser	missense_variant	2/5	1	NM_001659.3	ENSP00000256682.4
ENSG00000272822	ENST00000398092.4	c.139C>T	p.Pro47Ser	missense_variant	2/5	3		ENSP00000438507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Seizure;C3714756:Intellectual disability;C4024899:Atrophy/Degeneration affecting the central nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital

-

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published in the peer-reviewed literature as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: FasanoG2021[Functionalstudy]) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;T;.;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.7	.;H;H;H;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;.;.
Polyphen		1.0	.;D;.;D;.;.
Vest4		0.58
MutPred		0.70		Gain of catalytic residue at P47 (P = 0);Gain of catalytic residue at P47 (P = 0);Gain of catalytic residue at P47 (P = 0);Gain of catalytic residue at P47 (P = 0);Gain of catalytic residue at P47 (P = 0);Gain of catalytic residue at P47 (P = 0);
MVP		0.93
MPC		2.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.97

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49334740;