Variant 12-48939762-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001659.3(ARF3):c.277G>A(p.Asp93Asn) 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

ARF3
NM_001659.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.90

Variant links:

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]

ARF3 links:

ENSG00000272822 (HGNC:):

ENSG00000272822 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

PP5

Variant 12-48939762-C-T is Pathogenic according to our data. Variant chr12-48939762-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1697212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARF3	NM_001659.3 link	c.277G>A	p.Asp93Asn	missense_variant	4/5	ENST00000256682.9	NP_001650.1	P61204-1A0A024R0Y6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARF3	ENST00000256682.9 link	c.277G>A	p.Asp93Asn	missense_variant	4/5	1	NM_001659.3	ENSP00000256682.4		P61204-1
ENSG00000272822	ENST00000398092.4 link	c.277G>A	p.Asp93Asn	missense_variant	4/5	3		ENSP00000438507.1		F5H423

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autism;C0085271:Self-injurious behavior;C0262444:Abnormality of the dentition;C0454644:Delayed speech and language development;C0557874:Global developmental delay;C1839816:Long neck;C1848657:Long ear;C1854301:Motor delay;C4022738:Neurodevelopmental delay;C4022906:Delayed early-childhood social milestone development;C4551485:Clinodactyly;C4551488:Bifid uvula

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Mar 21, 2023

_x000D_ Criteria applied: PS3, PM2_SUP, PM6_SUP, PP3 -

Hypotonia;C2051831:Pectus excavatum;C3714756:Intellectual disability;C4024899:Atrophy/Degeneration affecting the central nervous system;C4551563:Microcephaly

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Sep 04, 2023

ACMG categories: PS1,PS4,PM2,PM6 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2024

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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 36369169) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

.;T;.;T;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;.;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.92

D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.7

.;H;.;H;.

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-4.6

D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;.

Polyphen

1.0

.;D;.;D;.

Vest4

0.96

MutPred

0.80

Gain of catalytic residue at D96 (P = 0.0319);Gain of catalytic residue at D96 (P = 0.0319);.;Gain of catalytic residue at D96 (P = 0.0319);Gain of catalytic residue at D96 (P = 0.0319);

MVP

0.94

MPC

2.4

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.82

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: -5

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over