4-122827149-G-T

Variant names:

• chr4-122827149-G-T
• rs1386563271
• ENST00000264498.9:c.374G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002006.6(FGF2):​c.374G>T​(p.Gly125Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000809 in 1,235,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G125E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: FGF2 NM_002006.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.709
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19063655).

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.-26G>T		5_prime_UTR	Exon 1 of 3	NP_001348594.1	D9ZGF5
	FGF2	NM_002006.6		c.374G>T	p.Gly125Val	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.374G>T	p.Gly125Val	missense	Exon 1 of 3	ENSP00000264498.4	P09038-4
	FGF2	ENST00000644866.2	MANE Select	c.-26G>T		5_prime_UTR	Exon 1 of 3	ENSP00000494222.1	P09038-2
	FGF2	ENST00000608478.1	TSL:1	c.-26G>T		5_prime_UTR	Exon 1 of 3	ENSP00000477134.1	P09038-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.09e-7 AC: 1 AN: 1235942 Hom.: 0 Cov.: 32 AF XY: 0.00000166 AC XY: 1 AN XY: 601166

African (AFR) AF: 0.00 AC: 0 AN: 25286

American (AMR) AF: 0.00 AC: 0 AN: 18458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19312

East Asian (EAS) AF: 0.00 AC: 0 AN: 27424

South Asian (SAS) AF: 0.00 AC: 0 AN: 55486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3518

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 1000318

Other (OTH) AF: 0.00 AC: 0 AN: 50344

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.6
DANN	Benign	0.86
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0096	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.71
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.13	N
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
MutPred		0.22		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.34
ClinPred		0.13	T
GERP RS		-1.7
PromoterAI		-0.13	Neutral
Varity_R		0.025
gMVP		0.11
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: rs1386563271; hg19: chr4-123748304;