Variant 4-80274959-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004464.4(FGF5):c.406G>A(p.Val136Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,600,860 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 4 hom. )

Consequence

FGF5
NM_004464.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.14

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:

FGF5 (HGNC:):

FGF5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF5	NM_004464.4 linkuse as main transcript	c.406G>A	p.Val136Ile	missense_variant	2/3	ENST00000312465.12	NP_004455.2	P12034-1Q8NBG6A0A7U3L5M4
FGF5	NM_001291812.2 linkuse as main transcript	c.-24G>A		5_prime_UTR_variant	2/3		NP_001278741.1	Q8NBG6
FGF5	NM_033143.2 linkuse as main transcript	c.355+7780G>A		intron_variant			NP_149134.1	P12034-2Q8NBG6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FGF5	ENST00000312465.12 linkuse as main transcript	c.406G>A	p.Val136Ile	missense_variant	2/3	1	NM_004464.4	ENSP00000311697.7	P12034-1
FGF5	ENST00000456523.3 linkuse as main transcript	c.355+7780G>A		intron_variant		1		ENSP00000398353.3	P12034-2
FGF5	ENST00000503413.1 linkuse as main transcript	n.355G>A		non_coding_transcript_exon_variant	2/3	2
FGF5	ENST00000507780.1 linkuse as main transcript	n.289G>A		non_coding_transcript_exon_variant	2/5	3		ENSP00000423903.1	H0Y9E2

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000309

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000228

AC:

AN:

245968

Hom.:

AF XY:

0.000240

AC XY:

AN XY:

133214

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.000393

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000301

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000259

Gnomad OTH exome

AF:

0.000673

GnomAD4 exome

AF:

0.000249

AC:

361

AN:

1448758

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

181

AN XY:

721018

show subpopulations

Gnomad4 AFR exome

AF:

0.000213

Gnomad4 AMR exome

AF:

0.000435

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000142

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000207

Gnomad4 OTH exome

AF:

0.000585

GnomAD4 genome

AF:

0.000210

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000311

Hom.:

Bravo

AF:

0.000325

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000272

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

Dec 13, 2022

The c.406G>A (p.V136I) alteration is located in exon 2 (coding exon 2) of the FGF5 gene. This alteration results from a G to A substitution at nucleotide position 406, causing the valine (V) at amino acid position 136 to be replaced by an isoleucine (I). 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

0.086

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Benign

0.047

MetaRNN

Uncertain

0.70

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.71

REVEL

Uncertain

0.43

Sift

Benign

0.045

Sift4G

Benign

0.092

Polyphen

0.99

Vest4

0.76

MVP

0.88

MPC

0.36

ClinPred

0.070

GERP RS

5.5

Varity_R

0.30

gMVP

0.35

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