Genetic Variant AGGF1:p.Pro262Leu (chr5-77039634-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018046.5(AGGF1):c.785C>T(p.Pro262Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,612,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P262S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

AGGF1
NM_018046.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.72

Variant links:

Genes affected

AGGF1 (HGNC:24684): (angiogenic factor with G-patch and FHA domains 1) This gene encodes an angiogenic factor that promotes proliferation of endothelial cells. Mutations in this gene are associated with a susceptibility to Klippel-Trenaunay syndrome. Pseudogenes of this gene are found on chromosomes 3, 4, 10 and 16.[provided by RefSeq, Sep 2010]

AGGF1 links:

ENSG00000285000 (HGNC:):

ENSG00000285000 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1377373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGGF1	NM_018046.5 link	c.785C>T	p.Pro262Leu	missense_variant	Exon 5 of 14	ENST00000312916.12	NP_060516.2	Q8N302-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGGF1	ENST00000312916.12 link	c.785C>T	p.Pro262Leu	missense_variant	Exon 5 of 14	1	NM_018046.5	ENSP00000316109.7	Q8N302-1
AGGF1	ENST00000502408.1 link	n.*511C>T		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000420874.1	H0Y8F8
ENSG00000285000	ENST00000646704.1 link	n.650C>T		non_coding_transcript_exon_variant	Exon 5 of 16			ENSP00000495089.1	A0A2R8YFF1
AGGF1	ENST00000502408.1 link	n.*511C>T		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000420874.1	H0Y8F8

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250808

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135600

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460870

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3470

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.785C>T (p.P262L) alteration is located in exon 5 (coding exon 5) of the AGGF1 gene. This alteration results from a C to T substitution at nucleotide position 785, causing the proline (P) at amino acid position 262 to be replaced by a leucine (L). 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

0.070

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.90

DEOGEN2

Benign

0.0053

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.58

M_CAP

Benign

0.047

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.41

REVEL

Benign

0.24

Sift

Benign

0.12

Sift4G

Benign

0.24

Polyphen

0.028

Vest4

0.32

MutPred

0.24

Gain of sheet (P = 0.0266);

MVP

0.77

MPC

0.19

ClinPred

0.098

GERP RS

5.1

Varity_R

0.029

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over