chr4-122826977-C-G

Position:

• chr4-122826977-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001361665.2(FGF2):​c.-198C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,309,714 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: FGF2 NM_001361665.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.624

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14717159).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.-198C>G		5_prime_UTR_variant	1/3	ENST00000644866.2	NP_001348594.1
FGF2	NM_002006.6	c.202C>G	p.Arg68Gly	missense_variant	1/3		NP_001997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000264498.9	c.202C>G	p.Arg68Gly	missense_variant	1/3	1		ENSP00000264498.4
FGF2	ENST00000644866.2	c.-198C>G		5_prime_UTR_variant	1/3		NM_001361665.2	ENSP00000494222.1
FGF2	ENST00000608478.1	c.-198C>G		5_prime_UTR_variant	1/3	1		ENSP00000477134.1

Frequencies

GnomAD3 genomes AF: 0.0000663 AC: 10 AN: 150732 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000462

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000917 AC: 2 AN: 21808 Hom.: 0 AF XY: 0.0000755 AC XY: 1 AN XY: 13250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000238

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 4 AN: 1158878 Hom.: 0 Cov.: 32 AF XY: 0.00000358 AC XY: 2 AN XY: 558358

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000484

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000663 AC: 10 AN: 150836 Hom.: 0 Cov.: 31 AF XY: 0.0000407 AC XY: 3 AN XY: 73708

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000461

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000392

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000113

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

Dec 18, 2023

The c.202C>G (p.R68G) alteration is located in exon 1 (coding exon 1) of the FGF2 gene. This alteration results from a C to G substitution at nucleotide position 202, causing the arginine (R) at amino acid position 68 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	0.062
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.34	T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.040	N;.
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.61	T;T
Polyphen		0.0050	.;B
MutPred		0.27		Loss of methylation at R68 (P = 0.0231);Loss of methylation at R68 (P = 0.0231);
MVP		0.59
ClinPred		0.18	T
GERP RS		-0.16
Varity_R		0.18
gMVP		0.099

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: rs1048407271; hg19: chr4-123748132;