chr4-80286410-A-G

Position:

• chr4-80286410-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004464.4(FGF5):​c.545A>G​(p.Glu182Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGF5 NM_004464.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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 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=0.09468746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF5	NM_004464.4	c.545A>G	p.Glu182Gly	missense_variant	3/3	ENST00000312465.12	NP_004455.2
FGF5	NM_001291812.2	c.116A>G	p.Glu39Gly	missense_variant	3/3		NP_001278741.1
FGF5	NM_033143.2	c.*69A>G		3_prime_UTR_variant	2/2		NP_149134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF5	ENST00000312465.12	c.545A>G	p.Glu182Gly	missense_variant	3/3	1	NM_004464.4	ENSP00000311697.7
FGF5	ENST00000456523.3	c.*69A>G		3_prime_UTR_variant	2/2	1		ENSP00000398353.3
FGF5	ENST00000503413.1	n.494A>G		non_coding_transcript_exon_variant	3/3	2
FGF5	ENST00000507780.1	n.342+11398A>G		intron_variant		3		ENSP00000423903.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.545A>G (p.E182G) alteration is located in exon 3 (coding exon 3) of the FGF5 gene. This alteration results from a A to G substitution at nucleotide position 545, causing the glutamic acid (E) at amino acid position 182 to be replaced by a glycine (G). 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	0.096
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.093
Sift	Benign	0.26	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.049
MutPred		0.38		Loss of stability (P = 0.0123);
MVP		0.63
MPC		0.097
ClinPred		0.27	T
GERP RS		5.8
Varity_R		0.067
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-81207564; COSMIC: COSV56889321;