4-122826956-G-A

Position:

• chr4-122826956-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The ENST00000264498.9(FGF2):​c.181G>A​(p.Gly61Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,197,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: FGF2 ENST00000264498.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0530

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2723368).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.-219G>A		5_prime_UTR_variant	1/3	ENST00000644866.2	NP_001348594.1
FGF2	NM_002006.6	c.181G>A	p.Gly61Ser	missense_variant	1/3		NP_001997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000264498.9	c.181G>A	p.Gly61Ser	missense_variant	1/3	1		ENSP00000264498
FGF2	ENST00000644866.2	c.-219G>A		5_prime_UTR_variant	1/3		NM_001361665.2	ENSP00000494222	P1
FGF2	ENST00000608478.1	c.-219G>A		5_prime_UTR_variant	1/3	1		ENSP00000477134	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000501 AC: 6 AN: 1197628 Hom.: 0 Cov.: 32 AF XY: 0.00000517 AC XY: 3 AN XY: 580656

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: 0.0000404

Gnomad4 FIN exome AF: 0.0000353

Gnomad4 NFE exome AF: 0.00000205

Gnomad4 OTH exome AF: 0.0000207

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Jan 22, 2024

The c.181G>A (p.G61S) alteration is located in exon 1 (coding exon 1) of the FGF2 gene. This alteration results from a G to A substitution at nucleotide position 181, causing the glycine (G) at amino acid position 61 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.48	T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.060	N;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.12	T;T
Polyphen		0.89	.;P
MutPred		0.30		Gain of phosphorylation at G61 (P = 2e-04);Gain of phosphorylation at G61 (P = 2e-04);
MVP		0.85
ClinPred		0.37	T
GERP RS		2.0
Varity_R		0.048
gMVP		0.087

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: rs1245576530; hg19: chr4-123748111;