chr1-228097257-C-T

Variant names:

• chr1-228097257-C-T
• rs1571844539
• NM_001658.4:c.143C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_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. 13/22 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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.84
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001658.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 4.1509 (above the threshold of 3.09). GenCC associations: The gene is linked to periventricular nodular heterotopia 8, periventricular nodular heterotopia.
• 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 VariationId is 690284.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001658.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARF1	NM_001658.4	MANE Select	c.143C>T	p.Thr48Ile	missense	Exon 2 of 5	NP_001649.1	P84077
	ARF1	NM_001024226.2		c.143C>T	p.Thr48Ile	missense	Exon 2 of 5	NP_001019397.1	P84077
	ARF1	NM_001024227.1		c.143C>T	p.Thr48Ile	missense	Exon 2 of 5	NP_001019398.1	P84077

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARF1	ENST00000272102.10	TSL:1 MANE Select	c.143C>T	p.Thr48Ile	missense	Exon 2 of 5	ENSP00000272102.5	P84077
	ARF1	ENST00000470558.5	TSL:2	c.143C>T	p.Thr48Ile	missense	Exon 2 of 5	ENSP00000514654.1	P84077
	ARF1	ENST00000478336.5	TSL:2	c.143C>T	p.Thr48Ile	missense	Exon 2 of 5	ENSP00000514657.1	P84077

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Periventricular nodular heterotopia 8 (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.79		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
Mutation Taster		=31/69	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1571844539; hg19: chr1-228284958;