2-227523863-C-G

Variant names:

• chr2-227523863-C-G
• rs921991135
• NM_004504.5:c.478C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004504.5(AGFG1):​c.478C>G​(p.Leu160Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L160M) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: AGFG1 NM_004504.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.50
• Publications: 0 publications found

Genes affected

AGFG1 (HGNC:5175): (ArfGAP with FG repeats 1) The protein encoded by this gene is related to nucleoporins, a class of proteins that mediate nucleocytoplasmic transport. The encoded protein binds the activation domain of the human immunodeficiency virus Rev protein when Rev is assembled onto its RNA target, and is required for the nuclear export of Rev-directed RNAs. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32554847).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004504.5. 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
	AGFG1	NM_004504.5	MANE Select	c.478C>G	p.Leu160Val	missense	Exon 4 of 13	NP_004495.2
	AGFG1	NM_001135187.2		c.478C>G	p.Leu160Val	missense	Exon 4 of 14	NP_001128659.1	P52594-4
	AGFG1	NM_001135188.2		c.478C>G	p.Leu160Val	missense	Exon 4 of 13	NP_001128660.1	P52594-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGFG1	ENST00000310078.13	TSL:1 MANE Select	c.478C>G	p.Leu160Val	missense	Exon 4 of 13	ENSP00000312059.7	P52594-1
	AGFG1	ENST00000409171.5	TSL:1	c.478C>G	p.Leu160Val	missense	Exon 4 of 13	ENSP00000387218.1	P52594-3
	AGFG1	ENST00000373671.7	TSL:1	c.478C>G	p.Leu160Val	missense	Exon 4 of 12	ENSP00000362775.3	P52594-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74246

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.012	D
Sift4G	Benign	0.081	T
Polyphen		0.64	P
Vest4		0.51
MutPred		0.22		Gain of methylation at K161 (P = 0.0334)
MVP		0.38
MPC		0.59
ClinPred		0.96	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.38
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs921991135; hg19: chr2-228388579;