20-49018885-A-T

Variant names:

• chr20-49018885-A-T
• rs2091546734
• NM_006420.3:c.4511A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006420.3(ARFGEF2):​c.4511A>T​(p.Asp1504Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARFGEF2 NM_006420.3 missense, splice_region
• Scores: Splicing: ADA: 0.2697
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.41

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.4511A>T	p.Asp1504Val	missense_variant, splice_region_variant	Exon 34 of 39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.4508A>T	p.Asp1503Val	missense_variant, splice_region_variant	Exon 34 of 39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.3947A>T	p.Asp1316Val	missense_variant, splice_region_variant	Exon 32 of 37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.4511A>T	p.Asp1504Val	missense_variant, splice_region_variant	Exon 34 of 39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4511A>T (p.D1504V) alteration is located in exon 34 (coding exon 34) of the ARFGEF2 gene. This alteration results from a A to T substitution at nucleotide position 4511, causing the aspartic acid (D) at amino acid position 1504 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.041
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.050	T
Polyphen		0.0	B
Vest4		0.80
MutPred		0.35		Gain of methylation at K1501 (P = 0.053);
MVP		0.83
MPC		0.66
ClinPred		0.86	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.27
dbscSNV1_RF	Benign	0.57
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: rs2091546734; hg19: chr20-47635422;