rs147534008

Positions:

chr20-48973263-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_006420.3(ARFGEF2):c.1644G>A(p.Glu548Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,614,138 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 5 hom. )

Consequence

ARFGEF2
NM_006420.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.855

Variant links:

Genes affected

ARFGEF2 (HGNC:15853): (ADP ribosylation factor guanine nucleotide exchange factor 2) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Jul 2008]

ARFGEF2 links:

ARFGEF2 (HGNC:):

ARFGEF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 20-48973263-G-A is Benign according to our data. Variant chr20-48973263-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128432.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.

BP7

Synonymous conserved (PhyloP=0.855 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000965 (147/152272) while in subpopulation NFE AF= 0.00157 (107/68022). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3 linkuse as main transcript	c.1644G>A	p.Glu548Glu	synonymous_variant	12/39	ENST00000371917.5	NP_006411.2	Q9Y6D5Q86TH5Q59FR3
ARFGEF2	NM_001410846.1 linkuse as main transcript	c.1641G>A	p.Glu547Glu	synonymous_variant	12/39		NP_001397775.1
ARFGEF2	XM_047439832.1 linkuse as main transcript	c.1080G>A	p.Glu360Glu	synonymous_variant	10/37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5 linkuse as main transcript	c.1644G>A	p.Glu548Glu	synonymous_variant	12/39	1	NM_006420.3	ENSP00000360985.4		Q9Y6D5

Frequencies

GnomAD3 genomes

AF:

0.000966

AC:

147

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000780

AC:

196

AN:

251430

Hom.:

AF XY:

0.000787

AC XY:

107

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00147

AC:

2145

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1055

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00173

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.000965

AC:

147

AN:

152272

Hom.:

Cov.:

AF XY:

0.000954

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00157

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.000910

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ARFGEF2: BP4, BP7 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 13, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Periventricular heterotopia with microcephaly, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.6

DANN

Benign

0.56

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over