rs61748373

chr20-48995838-G-Achr20-48995838-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006420.3(ARFGEF2):c.3177G>A(p.Ser1059=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,148 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1059S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (10 hom., cov: 32)
  • Exomes 𝑓: 0.011 (88 hom.)
• Consequence: ARFGEF2 NM_006420.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -6.09

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 20-48995838-G-A is Benign according to our data. Variant chr20-48995838-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128436.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr20-48995838-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00758 (1155/152290) while in subpopulation NFE AF= 0.0114 (776/68024). AF 95% confidence interval is 0.0107. There are 10 homozygotes in gnomad4. There are 562 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARFGEF2	NM_006420.3	c.3177G>A	p.Ser1059=	synonymous_variant	23/39	ENST00000371917.5
ARFGEF2	NM_001410846.1	c.3174G>A	p.Ser1058=	synonymous_variant	23/39
ARFGEF2	XM_047439832.1	c.2613G>A	p.Ser871=	synonymous_variant	21/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.3177G>A	p.Ser1059=	synonymous_variant	23/39	1	NM_006420.3	P4

Frequencies

GnomAD3 genomes AF: 0.00760 AC: 1156 AN: 152172 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00784 AC: 1972 AN: 251492 Hom.: 17 AF XY: 0.00812 AC XY: 1103 AN XY: 135920

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00428

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.0107 AC: 15599 AN: 1461858 Hom.: 88 Cov.: 31 AF XY: 0.0105 AC XY: 7643 AN XY: 727236

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00427

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.00843

GnomAD4 genome AF: 0.00758 AC: 1155 AN: 152290 Hom.: 10 Cov.: 32 AF XY: 0.00755 AC XY: 562 AN XY: 74466

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0160

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00672 Hom.: 1

Bravo AF: 0.00640

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 21, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ARFGEF2: BP4, BP7, BS1, BS2 -

Periventricular heterotopia with microcephaly, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.74
Cadd	Benign	0.87
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61748373; hg19: chr20-47612375;