rs73113975

Positions:

• chr20-48941880-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.169C>T​(p.Pro57Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00741 in 1,614,242 control chromosomes in the GnomAD database, including 58 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 0.0054 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (54 hom.)
• Consequence: ARFGEF2 NM_006420.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.78

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 in gene, where missense usually causes diseases (based on misZ statistic), ARFGEF2. . Gene score misZ 2.5971 (greater than the threshold 3.09). Trascript score misZ 4.3519 (greater than threshold 3.09). GenCC has associacion of gene with periventricular nodular heterotopia, periventricular heterotopia with microcephaly, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006720543).
• BP6: Variant 20-48941880-C-T is Benign according to our data. Variant chr20-48941880-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128433.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=4}. Variant chr20-48941880-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00536 (817/152360) while in subpopulation NFE AF= 0.00954 (649/68032). AF 95% confidence interval is 0.00893. There are 4 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.169C>T	p.Pro57Ser	missense_variant	3/39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.169C>T	p.Pro57Ser	missense_variant	3/39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.-288-9443C>T		intron_variant			XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.169C>T	p.Pro57Ser	missense_variant	3/39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 816 AN: 152242 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00954

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00525 AC: 1321 AN: 251490 Hom.: 5 AF XY: 0.00526 AC XY: 715 AN XY: 135920

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00939

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00762 AC: 11142 AN: 1461882 Hom.: 54 Cov.: 32 AF XY: 0.00752 AC XY: 5470 AN XY: 727248

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00351

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.00230

Gnomad4 NFE exome AF: 0.00928

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.00536 AC: 817 AN: 152360 Hom.: 4 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74508

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00954

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00817 Hom.: 6

Bravo AF: 0.00505

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00559 AC: 679

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.00907

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2016	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	Eurofins Ntd Llc (ga)	Dec 28, 2016	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 24, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ARFGEF2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 26, 2017	- -

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Benign	0.72
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.087
Sift	Benign	0.28	T
Sift4G	Benign	0.14	T
Polyphen		0.31	B
Vest4		0.20
MVP		0.38
MPC		0.43
ClinPred		0.055	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.40

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: rs73113975; hg19: chr20-47558417;