4-122876362-A-G

Position:

• chr4-122876362-A-G

Variant summary

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

The NM_001361665.2(FGF2):​c.220A>G​(p.Ile74Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGF2 NM_001361665.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.220A>G	p.Ile74Val	missense_variant	2/3	ENST00000644866.2	NP_001348594.1
FGF2	NM_002006.6	c.619A>G	p.Ile207Val	missense_variant	2/3		NP_001997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000644866.2	c.220A>G	p.Ile74Val	missense_variant	2/3		NM_001361665.2	ENSP00000494222.1
FGF2	ENST00000264498.9	c.619A>G	p.Ile207Val	missense_variant	2/3	1		ENSP00000264498.4
FGF2	ENST00000608478.1	c.220A>G	p.Ile74Val	missense_variant	2/3	1		ENSP00000477134.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461514 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jul 05, 2024

The c.619A>G (p.I207V) alteration is located in exon 2 (coding exon 2) of the FGF2 gene. This alteration results from a A to G substitution at nucleotide position 619, causing the isoleucine (I) at amino acid position 207 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	0.67
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;.;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.8	.;M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.89	N;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.020	D;D;D;.
Polyphen		0.74	.;P;.;.
Vest4		0.70
MutPred		0.68		Gain of methylation at K208 (P = 0.0612);Gain of methylation at K208 (P = 0.0612);.;.;
MVP		0.81
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.26
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-123797517; COSMIC: COSV52648836;