NM_006420.3:c.-43G>A

Variant names:

• chr20-48921847-G-A
• rs370864802
• NM_006420.3:c.-43G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006420.3(ARFGEF2):​c.-43G>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 0.000696 in 1,487,502 control chromosomes in the GnomAD database, including 3 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 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (3 hom.)
• Consequence: ARFGEF2 NM_006420.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0220
• 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: DEFINITIVE, 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 20-48921847-G-A is Benign according to our data. Variant chr20-48921847-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 338679.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000573 (87/151890) while in subpopulation NFE AF = 0.000957 (65/67930). AF 95% confidence interval is 0.00077. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006420.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGEF2	NM_006420.3	MANE Select	c.-43G>A		5_prime_UTR	Exon 1 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.-43G>A		5_prime_UTR	Exon 1 of 39	NP_001397775.1	A0A7P0T7Z2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGEF2	ENST00000371917.5	TSL:1 MANE Select	c.-43G>A		5_prime_UTR	Exon 1 of 39	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000939861.1		c.-43G>A		5_prime_UTR	Exon 1 of 39	ENSP00000609920.1
	ARFGEF2	ENST00000963182.1		c.-43G>A		5_prime_UTR	Exon 1 of 37	ENSP00000633241.1

Frequencies

GnomAD3 genomes AF: 0.000573 AC: 87 AN: 151890 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000957

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000646 AC: 73 AN: 112960 AF XY: 0.000585

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000633

Gnomad ASJ exome AF: 0.00213

Gnomad EAS exome AF: 0.000182

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000643

GnomAD4 exome AF: 0.000710 AC: 948 AN: 1335612 Hom.: 3 Cov.: 31 AF XY: 0.000706 AC XY: 465 AN XY: 658490

African (AFR) AF: 0.000112 AC: 3 AN: 26774

American (AMR) AF: 0.000800 AC: 24 AN: 30010

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 46 AN: 22784

East Asian (EAS) AF: 0.0000682 AC: 2 AN: 29340

South Asian (SAS) AF: 0.00 AC: 0 AN: 74258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5132

European-Non Finnish (NFE) AF: 0.000789 AC: 825 AN: 1045752

Other (OTH) AF: 0.000880 AC: 48 AN: 54528

GnomAD4 genome AF: 0.000573 AC: 87 AN: 151890 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74200

African (AFR) AF: 0.000121 AC: 5 AN: 41384

American (AMR) AF: 0.000525 AC: 8 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000957 AC: 65 AN: 67930

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00150 Hom.: 1

Bravo AF: 0.000638

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	ARFGEF2-related disorder (1)
-	-	1	not provided (1)
-	1	-	Periventricular heterotopia with microcephaly, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		-0.022
PromoterAI		-0.023	Neutral

Splicing

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

Other links and lift over

dbSNP: rs370864802; hg19: chr20-47538384;