4-80274981-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004464.4(FGF5):c.428C>T(p.Ala143Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,583,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

FGF5
NM_004464.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.21

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FGF5	NM_004464.4 linkuse as main transcript	c.428C>T	p.Ala143Val	missense_variant	2/3	ENST00000312465.12
FGF5	NM_001291812.2 linkuse as main transcript	c.-2C>T		5_prime_UTR_variant	2/3
FGF5	NM_033143.2 linkuse as main transcript	c.355+7802C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF5	ENST00000312465.12 linkuse as main transcript	c.428C>T	p.Ala143Val	missense_variant	2/3	1	NM_004464.4	P1	P12034-1
FGF5	ENST00000456523.3 linkuse as main transcript	c.355+7802C>T		intron_variant		1			P12034-2
FGF5	ENST00000503413.1 linkuse as main transcript	n.377C>T		non_coding_transcript_exon_variant	2/3	2
FGF5	ENST00000507780.1 linkuse as main transcript	c.311C>T	p.Ala104Val	missense_variant, NMD_transcript_variant	2/5	3

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000559

AC:

AN:

1432030

Hom.:

Cov.:

AF XY:

0.00000421

AC XY:

AN XY:

713424

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

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:

0.00000550

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151658

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74022

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000264

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

Sep 15, 2021

The c.428C>T (p.A143V) alteration is located in exon 2 (coding exon 2) of the FGF5 gene. This alteration results from a C to T substitution at nucleotide position 428, causing the alanine (A) at amino acid position 143 to be replaced by a valine (V). 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

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0060

Polyphen

0.95

Vest4

0.97

MutPred

0.72

Loss of disorder (P = 0.0839);

MVP

0.86

MPC

0.43

ClinPred

0.99

GERP RS

5.5

Varity_R

0.92

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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