4-122827062-G-T

Variant names:

• chr4-122827062-G-T
• rs1725652120
• NM_001361665.2:c.-113G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001361665.2(FGF2):​c.-113G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 955,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: FGF2 NM_001361665.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.682
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33324513).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001361665.2. 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.-113G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001348594.1	D9ZGF5
	FGF2	NM_001361665.2	MANE Select	c.-113G>T		5_prime_UTR	Exon 1 of 3	NP_001348594.1	D9ZGF5
	FGF2	NM_002006.6		c.287G>T	p.Arg96Leu	missense	Exon 1 of 3	NP_001997.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF2	ENST00000644866.2	MANE Select	c.-113G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000494222.1	P09038-2
	FGF2	ENST00000608478.1	TSL:1	c.-113G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000477134.1	P09038-2
	FGF2	ENST00000264498.9	TSL:1	c.287G>T	p.Arg96Leu	missense	Exon 1 of 3	ENSP00000264498.4	P09038-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 955726 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 448888

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18788

American (AMR) AF: 0.00 AC: 0 AN: 4648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9154

East Asian (EAS) AF: 0.00 AC: 0 AN: 13592

South Asian (SAS) AF: 0.00 AC: 0 AN: 18400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2232

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840500

Other (OTH) AF: 0.00 AC: 0 AN: 35004

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.68
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.15	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.96	D
MutPred		0.41		Loss of methylation at R96 (P = 8e-04)
MVP		0.89
ClinPred		0.56	D
GERP RS		1.1
PromoterAI		0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.21
gMVP		0.24
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: rs1725652120; hg19: chr4-123748217;