chr1-228097257-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_001658.4(ARF1):​c.143C>T​(p.Thr48Ile) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ARF1
NM_001658.4 missense

Scores

15
2
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.84
Variant links:
Genes affected
ARF1 (HGNC:652): (ADP ribosylation factor 1) ADP-ribosylation factor 1 (ARF1) is a member of the human ARF gene family. The family members encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking as activators of phospholipase D. The gene products, including 6 ARF proteins and 11 ARF-like proteins, constitute a 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. The ARF1 protein is localized to the Golgi apparatus and has a central role in intra-Golgi transport. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
MIR3620 (HGNC:38917): (microRNA 3620) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a chain ADP-ribosylation factor 1 (size 179) in uniprot entity ARF1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001658.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
Variant 1-228097257-C-T is Pathogenic according to our data. Variant chr1-228097257-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 690284.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARF1NM_001658.4 linkc.143C>T p.Thr48Ile missense_variant Exon 2 of 5 ENST00000272102.10 NP_001649.1 P84077A0A024R3Q0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARF1ENST00000272102.10 linkc.143C>T p.Thr48Ile missense_variant Exon 2 of 5 1 NM_001658.4 ENSP00000272102.5 P84077

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Periventricular nodular heterotopia 8 Pathogenic:1
Mar 22, 2019
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
D;D;D
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.85
.;.;D
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.7
H;H;H
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-5.1
D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.96
MutPred
0.79
Loss of glycosylation at T48 (P = 0.0238);Loss of glycosylation at T48 (P = 0.0238);Loss of glycosylation at T48 (P = 0.0238);
MVP
0.96
MPC
2.0
ClinPred
1.0
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.93
gMVP
0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1571844539; hg19: chr1-228284958; API