rs748489377

Variant names:

• chr3-57577356-C-G
• rs748489377
• NM_001660.4:c.290G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-57577356-C-G
• chr3-57577356-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001660.4(ARF4):​c.290G>C​(p.Arg97Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: ARF4 NM_001660.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17
• Publications: 1 publications found

Genes affected

ARF4 (HGNC:655): (ADP ribosylation factor 4) This gene is a member of the human ARF gene family whose members 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 5 ARF proteins and 11 ARF-like proteins and constitute one family of the RAS superfamily. The ARF proteins are categorized as class I, class II and class III; this gene is a class II member. The members of each class share a common gene organization. The ARF4 gene spans approximately 12kb and contains six exons and five introns. This gene is the most divergent member of the human ARFs. Conflicting map positions at 3p14 or 3p21 have been reported for this gene. [provided by RefSeq, Jul 2008]

PDE12 (HGNC:25386): (phosphodiesterase 12) Enables 3'-5'-exoribonuclease activity. Involved in several processes, including RNA metabolic process; cellular response to cytokine stimulus; and regulation of mitochondrial mRNA stability. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

PDE12 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001660.4. 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
	ARF4	NM_001660.4	MANE Select	c.290G>C	p.Arg97Pro	missense	Exon 4 of 6	NP_001651.1	P18085
	PDE12	NM_001322176.2		c.1387+17968C>G		intron	N/A	NP_001309105.1	A0ABB0MV04

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARF4	ENST00000303436.11	TSL:1 MANE Select	c.290G>C	p.Arg97Pro	missense	Exon 4 of 6	ENSP00000306010.6	P18085
	ARF4	ENST00000489843.1	TSL:3	c.-38G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000475828.1	U3KQF2
	ARF4	ENST00000948644.1		c.290G>C	p.Arg97Pro	missense	Exon 5 of 7	ENSP00000618703.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151960 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151960 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74212

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.049	D
Polyphen		0.77	P
Vest4		0.35
MutPred		0.54		Loss of sheet (P = 0.0315)
MVP		0.67
MPC		2.3
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.96
Mutation Taster		=27/73	disease causing

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: rs748489377; hg19: chr3-57563083;