20-49028544-T-A

Variant names:

• chr20-49028544-T-A
• rs587780281
• NM_006420.3:c.4939T>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.4939T>A​(p.Ser1647Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000493 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: ARFGEF2 NM_006420.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.02
• 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]

CSE1L-DT (HGNC:51232): (CSE1L divergent transcript)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.09192306).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000493 (72/1461874) while in subpopulation SAS AF = 0.000823 (71/86258). AF 95% confidence interval is 0.000668. There are 0 homozygotes in GnomAdExome4. There are 62 alleles in the male GnomAdExome4 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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGEF2	NM_006420.3	MANE Select	c.4939T>A	p.Ser1647Thr	missense	Exon 37 of 39	NP_006411.2
	ARFGEF2	NM_001410846.1		c.4936T>A	p.Ser1646Thr	missense	Exon 37 of 39	NP_001397775.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGEF2	ENST00000371917.5	TSL:1 MANE Select	c.4939T>A	p.Ser1647Thr	missense	Exon 37 of 39	ENSP00000360985.4
	ARFGEF2	ENST00000679436.1		c.4936T>A	p.Ser1646Thr	missense	Exon 37 of 39	ENSP00000504888.1
	ARFGEF2	ENST00000939861.1		c.4933T>A	p.Ser1645Thr	missense	Exon 37 of 39	ENSP00000609920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000111 AC: 28 AN: 251476 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000823 AC: 71 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.000157 AC: 19

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.13
Sift	Benign	0.44	T
Sift4G	Benign	0.29	T
Polyphen		0.038	B
Vest4		0.52
MutPred		0.27		Loss of disorder (P = 0.1008)
MVP		0.59
MPC		0.40
ClinPred		0.24	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.26
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs587780281; hg19: chr20-47645081; COSMIC: COSV100904587;