rs34203073

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_ModerateBP4_StrongBP6_Very_StrongBS1BS2

The NM_018046.5(AGGF1):c.397G>A(p.Glu133Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,410 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 33)

Exomes 𝑓: 0.014 ( 182 hom. )

Consequence

AGGF1
NM_018046.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.05

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 Benign. Variant got -18 ACMG points.

PS1

Transcript NM_018046.5 (AGGF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP4

Computational evidence support a benign effect (MetaRNN=0.0030573606).

BP6

Variant 5-77035624-G-A is Benign according to our data. Variant chr5-77035624-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 402345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-77035624-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0142 (20774/1461240) while in subpopulation MID AF= 0.026 (150/5760). AF 95% confidence interval is 0.0226. There are 182 homozygotes in gnomad4_exome. There are 10210 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGGF1	NM_018046.5 link	c.397G>A	p.Glu133Lys	missense_variant	Exon 3 of 14	ENST00000312916.12	NP_060516.2	Q8N302-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGGF1	ENST00000312916.12 link	c.397G>A	p.Glu133Lys	missense_variant	Exon 3 of 14	1	NM_018046.5	ENSP00000316109.7		Q8N302-1
ENSG00000285000	ENST00000646704.1 link	n.262G>A		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000495089.1		A0A2R8YFF1

Frequencies

GnomAD3 genomes

AF:

0.00998

AC:

1518

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0102

AC:

2555

AN:

251246

Hom.:

AF XY:

0.0102

AC XY:

1392

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00749

Gnomad ASJ exome

AF:

0.0268

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00281

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.0153

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0142

AC:

20774

AN:

1461240

Hom.:

182

Cov.:

AF XY:

0.0140

AC XY:

10210

AN XY:

726942

show subpopulations

Gnomad4 AFR exome

AF:

0.00272

Gnomad4 AMR exome

AF:

0.00790

Gnomad4 ASJ exome

AF:

0.0268

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00303

Gnomad4 FIN exome

AF:

0.00271

Gnomad4 NFE exome

AF:

0.0163

Gnomad4 OTH exome

AF:

0.0153

GnomAD4 genome

AF:

0.00997

AC:

1517

AN:

152170

Hom.:

Cov.:

AF XY:

0.00913

AC XY:

679

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00294

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.0280

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00395

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.0156

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0149

Hom.:

Bravo

AF:

0.0104

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0195

AC:

168

ExAC

AF:

0.00967

AC:

1174

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0186

EpiControl

AF:

0.0175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 14961121, 16443853) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGGF1: BP4, BS1, BS2 -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 185/13004=1.4% -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.6

DANN

Benign

0.95

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.48

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.79

N;N

REVEL

Benign

0.092

Sift

Benign

0.074

T;T

Sift4G

Benign

0.32

T;D

Polyphen

0.0020

B;B

Vest4

0.28

MPC

0.21

ClinPred

0.0029

GERP RS

1.1

Varity_R

0.027

gMVP

0.24

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

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