4-122826966-G-T

Variant names:

• chr4-122826966-G-T
• ENST00000264498.9:c.191G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002006.6(FGF2):​c.191G>T​(p.Arg64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,176,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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: 0.0000017 (0 hom.)
• Consequence: FGF2 NM_002006.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.97

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1572476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.-209G>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000644866.2	NP_001348594.1
FGF2	NM_002006.6	c.191G>T	p.Arg64Leu	missense_variant	Exon 1 of 3		NP_001997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000264498.9	c.191G>T	p.Arg64Leu	missense_variant	Exon 1 of 3	1		ENSP00000264498.4
FGF2	ENST00000644866	c.-209G>T		5_prime_UTR_variant	Exon 1 of 3		NM_001361665.2	ENSP00000494222.1
FGF2	ENST00000608478	c.-209G>T		5_prime_UTR_variant	Exon 1 of 3	1		ENSP00000477134.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000170 AC: 2 AN: 1176918 Hom.: 0 Cov.: 32 AF XY: 0.00000176 AC XY: 1 AN XY: 568624

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191G>T (p.R64L) alteration is located in exon 1 (coding exon 1) of the FGF2 gene. This alteration results from a G to T substitution at nucleotide position 191, causing the arginine (R) at amino acid position 64 to be replaced by a leucine (L). 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	0.094
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.4
DANN	Benign	0.95
DEOGEN2	Benign	0.33	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.46	T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.26	N;.
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.31	T;T
Polyphen		0.10	.;B
MutPred		0.25		Loss of methylation at R64 (P = 0.0122);Loss of methylation at R64 (P = 0.0122);
MVP		0.45
ClinPred		0.26	T
GERP RS		-0.68
Varity_R		0.11
gMVP		0.071

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: chr4-123748121;