4-80267067-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_004464.4(FGF5):c.243G>T(p.Trp81Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00193 in 1,614,240 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: FGF5 NM_004464.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.56

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019742876).
• BP6: Variant 4-80267067-G-T is Benign according to our data. Variant chr4-80267067-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 786515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF5	NM_004464.4	c.243G>T	p.Trp81Cys	missense_variant	1/3	ENST00000312465.12
FGF5	NM_033143.2	c.243G>T	p.Trp81Cys	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF5	ENST00000312465.12	c.243G>T	p.Trp81Cys	missense_variant	1/3	1	NM_004464.4	P1
FGF5	ENST00000456523.3	c.243G>T	p.Trp81Cys	missense_variant	1/2	1
FGF5	ENST00000380628.3	n.243G>T		non_coding_transcript_exon_variant	1/2	1
FGF5	ENST00000507780.1	c.126G>T	p.Trp42Cys	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152258 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

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: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00169 AC: 424 AN: 251104 Hom.: 1 AF XY: 0.00158 AC XY: 215 AN XY: 135808

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00197 AC: 2887 AN: 1461864 Hom.: 4 Cov.: 31 AF XY: 0.00196 AC XY: 1424 AN XY: 727238

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152376 Hom.: 1 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74514

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00231 Hom.: 0

Bravo AF: 0.00136

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00208 AC: 252

EpiCase AF: 0.00174

EpiControl AF: 0.00237

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 2018

- -

FGF5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.067	T;D
Polyphen		0.99	D;D
Vest4		0.60
MutPred		0.43		Loss of MoRF binding (P = 0.0198);Loss of MoRF binding (P = 0.0198);
MVP		0.74
MPC		0.52
ClinPred		0.073	T
GERP RS		5.4
Varity_R		0.28
gMVP		0.66

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

Other links and lift over

dbSNP: rs112475347; hg19: chr4-81188221;