4-122827062-G-C

Variant names:

• chr4-122827062-G-C
• rs1725652120
• ENST00000264498.9:c.287G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002006.6(FGF2):​c.287G>C​(p.Arg96Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000019 in 1,102,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R96Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: FGF2 NM_002006.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.682
• Publications: 0 publications found

Genes affected

FGF2 (HGNC:3676): (fibroblast growth factor 2) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members bind heparin and possess broad mitogenic and angiogenic activities. This protein has been implicated in diverse biological processes, such as limb and nervous system development, wound healing, and tumor growth. The mRNA for this gene contains multiple polyadenylation sites, and is alternatively translated from non-AUG (CUG) and AUG initiation codons, resulting in five different isoforms with distinct properties. The CUG-initiated isoforms are localized in the nucleus and are responsible for the intracrine effect, whereas, the AUG-initiated form is mostly cytosolic and is responsible for the paracrine and autocrine effects of this FGF. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2885376).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002006.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF2	NM_001361665.2	MANE Select	c.-113G>C		5_prime_UTR	Exon 1 of 3	NP_001348594.1	D9ZGF5
	FGF2	NM_002006.6		c.287G>C	p.Arg96Pro	missense	Exon 1 of 3	NP_001997.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF2	ENST00000264498.9	TSL:1	c.287G>C	p.Arg96Pro	missense	Exon 1 of 3	ENSP00000264498.4	P09038-4
	FGF2	ENST00000644866.2	MANE Select	c.-113G>C		5_prime_UTR	Exon 1 of 3	ENSP00000494222.1	P09038-2
	FGF2	ENST00000608478.1	TSL:1	c.-113G>C		5_prime_UTR	Exon 1 of 3	ENSP00000477134.1	P09038-2

Frequencies

GnomAD3 genomes AF: 0.00000680 AC: 1 AN: 146984 Hom.: 0 Cov.: 31

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000209 AC: 20 AN: 955724 Hom.: 0 Cov.: 30 AF XY: 0.0000223 AC XY: 10 AN XY: 448888

African (AFR) AF: 0.00 AC: 0 AN: 18788

American (AMR) AF: 0.00 AC: 0 AN: 4648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9152

East Asian (EAS) AF: 0.00 AC: 0 AN: 13592

South Asian (SAS) AF: 0.00 AC: 0 AN: 18400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13408

Middle Eastern (MID) AF: 0.000448 AC: 1 AN: 2232

European-Non Finnish (NFE) AF: 0.0000214 AC: 18 AN: 840500

Other (OTH) AF: 0.0000286 AC: 1 AN: 35004

GnomAD4 genome AF: 0.00000680 AC: 1 AN: 146984 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 1 AN XY: 71576

African (AFR) AF: 0.00 AC: 0 AN: 40572

American (AMR) AF: 0.00 AC: 0 AN: 14826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66242

Other (OTH) AF: 0.00 AC: 0 AN: 2020

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.68
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.45	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		0.046	B
MutPred		0.35		Loss of methylation at R96 (P = 8e-04)
MVP		0.74
ClinPred		0.52	D
GERP RS		1.1
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.28
gMVP		0.23
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs1725652120; hg19: chr4-123748217;