20-48921863-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006420.3(ARFGEF2):c.-27G>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 0.000634 in 1,508,868 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (5 hom.)
• Consequence: ARFGEF2 NM_006420.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.75

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=-0.51).
• BP6: Variant 20-48921863-G-A is Benign according to our data. Variant chr20-48921863-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377496.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000514 (78/151622) while in subpopulation SAS AF= 0.00642 (31/4830). AF 95% confidence interval is 0.00465. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARFGEF2	NM_006420.3	c.-27G>A		5_prime_UTR_variant	1/39	ENST00000371917.5
ARFGEF2	NM_001410846.1	c.-27G>A		5_prime_UTR_variant	1/39
ARFGEF2	XM_047439832.1	c.-436G>A		5_prime_UTR_variant	1/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.-27G>A		5_prime_UTR_variant	1/39	1	NM_006420.3	P4

Frequencies

GnomAD3 genomes AF: 0.000515 AC: 78 AN: 151512 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000442

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00155 AC: 188 AN: 121670 Hom.: 3 AF XY: 0.00186 AC XY: 122 AN XY: 65650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00712

Gnomad FIN exome AF: 0.000466

Gnomad NFE exome AF: 0.000419

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000648 AC: 879 AN: 1357246 Hom.: 5 Cov.: 31 AF XY: 0.000804 AC XY: 538 AN XY: 669174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00194

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00647

Gnomad4 FIN exome AF: 0.000459

Gnomad4 NFE exome AF: 0.000248

Gnomad4 OTH exome AF: 0.000949

GnomAD4 genome AF: 0.000514 AC: 78 AN: 151622 Hom.: 0 Cov.: 32 AF XY: 0.000432 AC XY: 32 AN XY: 74152

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.000442

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000329

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 19, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs550163684; hg19: chr20-47538400; COSMIC: COSV105927441;