chr4-122892274-C-G

Variant names:

• chr4-122892274-C-G
• NM_001361665.2:c.346C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001361665.2(FGF2):​c.346C>G​(p.Arg116Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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: Not reported in ClinVar
• Conservation: PhyloP100: 4.03

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]

NUDT6 (HGNC:8053): (nudix hydrolase 6) This gene overlaps and lies on the opposite strand from FGF2 gene, and is thought to be the FGF2 antisense gene. The two genes are independently transcribed, and their expression shows an inverse relationship, suggesting that this antisense transcript may regulate FGF2 expression. This gene has also been shown to have hormone-regulatory and antiproliferative actions in the pituitary that are independent of FGF2 expression. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.346C>G	p.Arg116Gly	missense_variant	Exon 3 of 3	ENST00000644866.2	NP_001348594.1
FGF2	NM_002006.6	c.745C>G	p.Arg249Gly	missense_variant	Exon 3 of 3		NP_001997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000644866.2	c.346C>G	p.Arg116Gly	missense_variant	Exon 3 of 3		NM_001361665.2	ENSP00000494222.1
FGF2	ENST00000264498.9	c.745C>G	p.Arg249Gly	missense_variant	Exon 3 of 3	1		ENSP00000264498.4
FGF2	ENST00000608478.1	c.346C>G	p.Arg116Gly	missense_variant	Exon 3 of 3	1		ENSP00000477134.1
NUDT6	ENST00000608639.1	n.57+358G>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461340 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727012

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;.;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	2.9	.;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.2	D;.;.;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.024	D;.;.;.
Sift4G	Benign	0.23	T;T;T;.
Polyphen		0.97	.;D;.;.
Vest4		0.72
MutPred		0.61		Loss of MoRF binding (P = 0.0514);Loss of MoRF binding (P = 0.0514);.;.;
MVP		0.87
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.69

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: chr4-123813429;