4-80286603-G-C

Variant summary

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

The NM_004464.4(FGF5):c.738G>C(p.Lys246Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,613,906 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 (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

FGF5
NM_004464.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

Variant links:

Genes affected

FGF5 (HGNC:3683): (fibroblast growth factor 5) 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. This gene was identified as an oncogene, which confers transforming potential when transfected into mammalian cells. Targeted disruption of the homolog of this gene in mouse resulted in the phenotype of abnormally long hair, which suggested a function as an inhibitor of hair elongation. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

FGF5 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=0.14392725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FGF5	NM_004464.4 linkuse as main transcript	c.738G>C	p.Lys246Asn	missense_variant	3/3	ENST00000312465.12
FGF5	NM_001291812.2 linkuse as main transcript	c.309G>C	p.Lys103Asn	missense_variant	3/3
FGF5	NM_033143.2 linkuse as main transcript	c.*262G>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF5	ENST00000312465.12 linkuse as main transcript	c.738G>C	p.Lys246Asn	missense_variant	3/3	1	NM_004464.4	P1	P12034-1
FGF5	ENST00000456523.3 linkuse as main transcript	c.*262G>C		3_prime_UTR_variant	2/2	1			P12034-2
FGF5	ENST00000503413.1 linkuse as main transcript	n.687G>C		non_coding_transcript_exon_variant	3/3	2
FGF5	ENST00000507780.1 linkuse as main transcript	c.342+11591G>C		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000159

AC:

AN:

251184

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.0000491

ExAC

AF:

0.0000165

AC:

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

Mar 03, 2022

The c.738G>C (p.K246N) alteration is located in exon 3 (coding exon 3) of the FGF5 gene. This alteration results from a G to C substitution at nucleotide position 738, causing the lysine (K) at amino acid position 246 to be replaced by an asparagine (N). 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

0.30

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.37

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.097

Eigen_PC

Benign

-0.0050

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

M_CAP

Benign

0.046

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0080

Polyphen

0.62

Vest4

0.12

MutPred

0.19

Loss of methylation at K246 (P = 0.0063);

MVP

0.73

MPC

0.093

ClinPred

0.17

GERP RS

4.8

Varity_R

0.16

gMVP

0.32

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