4-122827109-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The ENST00000264498.9(FGF2):c.334C>T(p.Arg112Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000191 in 1,253,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

FGF2
ENST00000264498.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.240

Variant links:

Genes affected

FGF2 (HGNC:3676): (fibroblast growth factor 2) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members bind heparin and possess broad mitogenic and angiogenic activities. This protein has been implicated in diverse biological processes, such as limb and nervous system development, wound healing, and tumor growth. The mRNA for this gene contains multiple polyadenylation sites, and is alternatively translated from non-AUG (CUG) and AUG initiation codons, resulting in five different isoforms with distinct properties. The CUG-initiated isoforms are localized in the nucleus and are responsible for the intracrine effect, whereas, the AUG-initiated form is mostly cytosolic and is responsible for the paracrine and autocrine effects of this FGF. [provided by RefSeq, Jul 2008]

FGF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a modified_residue Omega-N-methylarginine; alternate (size 0) in uniprot entity FGF2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.17608055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF2	NM_001361665.2 linkuse as main transcript	c.-66C>T		5_prime_UTR_variant	1/3	ENST00000644866.2
FGF2	NM_002006.6 linkuse as main transcript	c.334C>T	p.Arg112Trp	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF2	ENST00000264498.9 linkuse as main transcript	c.334C>T	p.Arg112Trp	missense_variant	1/3	1			P09038-4
FGF2	ENST00000644866.2 linkuse as main transcript	c.-66C>T		5_prime_UTR_variant	1/3		NM_001361665.2	P1	P09038-2
FGF2	ENST00000608478.1 linkuse as main transcript	c.-66C>T		5_prime_UTR_variant	1/3	1		P1	P09038-2

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000668

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1105194

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

527344

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000278

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000160

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148370

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72398

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000667

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000150

Gnomad4 OTH

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.334C>T (p.R112W) alteration is located in exon 1 (coding exon 1) of the FGF2 gene. This alteration results from a C to T substitution at nucleotide position 334, causing the arginine (R) at amino acid position 112 to be replaced by a tryptophan (W). 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

0.27

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Benign

-0.20

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.59

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.84

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.13

N;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.94

.;P

MutPred

0.32

Loss of methylation at R112 (P = 7e-04);Loss of methylation at R112 (P = 7e-04);

MVP

0.58

ClinPred

0.56

GERP RS

-0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.25

gMVP

0.18

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