4-122827076-G-C

Position:

• chr4-122827076-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000264498.9(FGF2):​c.301G>C​(p.Ala101Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGF2 ENST00000264498.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.787

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33848417).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.-99G>C		5_prime_UTR_variant	1/3	ENST00000644866.2	NP_001348594.1
FGF2	NM_002006.6	c.301G>C	p.Ala101Pro	missense_variant	1/3		NP_001997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000264498.9	c.301G>C	p.Ala101Pro	missense_variant	1/3	1		ENSP00000264498
FGF2	ENST00000644866.2	c.-99G>C		5_prime_UTR_variant	1/3		NM_001361665.2	ENSP00000494222	P1
FGF2	ENST00000608478.1	c.-99G>C		5_prime_UTR_variant	1/3	1		ENSP00000477134	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Jun 10, 2024

The c.301G>C (p.A101P) alteration is located in exon 1 (coding exon 1) of the FGF2 gene. This alteration results from a G to C substitution at nucleotide position 301, causing the alanine (A) at amino acid position 101 to be replaced by a proline (P). 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	0.080
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.34	.;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.17	N;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.23	T;T
Polyphen		0.99	.;D
MutPred		0.30		Gain of catalytic residue at A101 (P = 0.0126);Gain of catalytic residue at A101 (P = 0.0126);
MVP		0.83
ClinPred		0.72	D
GERP RS		2.1
Varity_R		0.21
gMVP		0.12

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: chr4-123748231;