rs143570842

chr20-48953763-C-Gchr20-48953763-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_006420.3(ARFGEF2):c.811C>G(p.Pro271Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,614,064 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (7 hom.)
• Consequence: ARFGEF2 NM_006420.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.695

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ARFGEF2
• BP4: Computational evidence support a benign effect (MetaRNN=0.009641409).
• BP6: Variant 20-48953763-C-G is Benign according to our data. Variant chr20-48953763-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128446.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr20-48953763-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00162 (247/152272) while in subpopulation NFE AF= 0.00295 (201/68034). AF 95% confidence interval is 0.00262. There are 0 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARFGEF2	NM_006420.3	c.811C>G	p.Pro271Ala	missense_variant	6/39	ENST00000371917.5
ARFGEF2	NM_001410846.1	c.811C>G	p.Pro271Ala	missense_variant	6/39
ARFGEF2	XM_047439832.1	c.247C>G	p.Pro83Ala	missense_variant	4/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.811C>G	p.Pro271Ala	missense_variant	6/39	1	NM_006420.3	P4

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00129 AC: 323 AN: 251010 Hom.: 2 AF XY: 0.00131 AC XY: 178 AN XY: 135722

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00260

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00285 AC: 4169 AN: 1461792 Hom.: 7 Cov.: 32 AF XY: 0.00277 AC XY: 2013 AN XY: 727194

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74452

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00295

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00167

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00123 AC: 150

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ARFGEF2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2022	See Variant Classification Assertion Criteria. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 04, 2016	- -

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. -

ARFGEF2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.3
Dann	Benign	0.30
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.080
Sift	Benign	0.50	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.15
MPC		0.41
ClinPred		0.0027	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.012
gMVP		0.32

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

Other links and lift over

dbSNP: rs143570842; hg19: chr20-47570300; COSMIC: COSV64213263;