rs375056092

Variant names:

• chr20-48921885-G-A
• rs375056092
• NM_006420.3:c.-5G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_006420.3(ARFGEF2):​c.-5G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,543,564 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ARFGEF2 NM_006420.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• periventricular heterotopia with microcephaly, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294533 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000211 (32/152010) while in subpopulation AMR AF = 0.000261 (4/15300). AF 95% confidence interval is 0.0000887. There are 1 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.-5G>A		5_prime_UTR_variant	Exon 1 of 39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.-5G>A		5_prime_UTR_variant	Exon 1 of 39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.-414G>A		5_prime_UTR_variant	Exon 1 of 37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.-5G>A		5_prime_UTR_variant	Exon 1 of 39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 32 AN: 151898 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00549

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000285 AC: 42 AN: 147168 AF XY: 0.000243

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00425

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000238

GnomAD4 exome AF: 0.000138 AC: 192 AN: 1391554 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 93 AN XY: 686524

African (AFR) AF: 0.0000327 AC: 1 AN: 30614

American (AMR) AF: 0.0000568 AC: 2 AN: 35232

Ashkenazi Jewish (ASJ) AF: 0.00503 AC: 125 AN: 24840

East Asian (EAS) AF: 0.00 AC: 0 AN: 34912

South Asian (SAS) AF: 0.00 AC: 0 AN: 78520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.0000363 AC: 39 AN: 1075354

Other (OTH) AF: 0.000434 AC: 25 AN: 57632

GnomAD4 genome AF: 0.000211 AC: 32 AN: 152010 Hom.: 1 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74330

African (AFR) AF: 0.0000723 AC: 3 AN: 41512

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00549 AC: 19 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67884

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000495 Hom.: 0

Bravo AF: 0.000162

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Periventricular heterotopia with microcephaly, autosomal recessive Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.45
CADD	Benign	17
DANN	Benign	0.92
PhyloP100		1.3
PromoterAI		0.091	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375056092; hg19: chr20-47538422;