Variant 5-171456729-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003862.3(FGF18):c.548C>T(p.Pro183Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00087 in 1,613,856 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 3 hom. )

Consequence

FGF18
NM_003862.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.75

Variant links:

Genes affected

FGF18 (HGNC:3674): (fibroblast growth factor 18) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth, and invasion. It has been shown in vitro that this protein is able to induce neurite outgrowth in PC12 cells. Studies of the similar proteins in mouse and chick suggested that this protein is a pleiotropic growth factor that stimulates proliferation in a number of tissues, most notably the liver and small intestine. Knockout studies of the similar gene in mice implied the role of this protein in regulating proliferation and differentiation of midline cerebellar structures. [provided by RefSeq, Jul 2008]

FGF18 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042396337).

BS2

High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF18	NM_003862.3 linkuse as main transcript	c.548C>T	p.Pro183Leu	missense_variant	5/5	ENST00000274625.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF18	ENST00000274625.6 linkuse as main transcript	c.548C>T	p.Pro183Leu	missense_variant	5/5	1	NM_003862.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

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:

0.00107

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000550

AC:

138

AN:

250762

Hom.:

AF XY:

0.000545

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.000373

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000902

AC:

1319

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000850

AC XY:

618

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000559

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.000566

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.000290

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:

0.00107

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000948

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000544

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.00113

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

Jun 18, 2021

The c.548C>T (p.P183L) alteration is located in exon 5 (coding exon 5) of the FGF18 gene. This alteration results from a C to T substitution at nucleotide position 548, causing the proline (P) at amino acid position 183 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

-0.42

BayesDel_noAF

Benign

-0.41

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.083

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.75

M_CAP

Benign

0.015

MetaRNN

Benign

0.042

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.81

MutationTaster

Benign

0.99

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.99

REVEL

Benign

0.11

Sift

Benign

0.64

Sift4G

Benign

0.46

Polyphen

0.61

Vest4

0.085

MVP

0.69

MPC

1.1

ClinPred

0.022

GERP RS

4.7

Varity_R

0.071

gMVP

0.56

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