4-122826977-C-T

Variant names:

• chr4-122826977-C-T
• rs1048407271
• NM_001361665.2:c.-198C>T

Variant summary

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

The NM_001361665.2(FGF2):​c.-198C>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 0.00000259 in 1,158,878 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: 0.0000026 (0 hom.)
• Consequence: FGF2 NM_001361665.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• 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 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=0.26177317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.-198C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	ENST00000644866.2	NP_001348594.1
FGF2	NM_001361665.2	c.-198C>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000644866.2	NP_001348594.1
FGF2	NM_002006.6	c.202C>T	p.Arg68Trp	missense_variant	Exon 1 of 3		NP_001997.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000644866	c.-198C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3		NM_001361665.2	ENSP00000494222.1
FGF2	ENST00000644866	c.-198C>T		5_prime_UTR_variant	Exon 1 of 3		NM_001361665.2	ENSP00000494222.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000259 AC: 3 AN: 1158878 Hom.: 0 Cov.: 32 AF XY: 0.00000179 AC XY: 1 AN XY: 558358

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: 0.00000313

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.0089	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.56	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.13	N;.
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.082	T;T
Polyphen		1.0	.;D
MutPred		0.27		Loss of methylation at R68 (P = 0.0231);Loss of methylation at R68 (P = 0.0231);
MVP		0.86
ClinPred		0.50	D
GERP RS		-0.16
Varity_R		0.11
gMVP		0.081

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;