4-122896930-C-G

Position:

• chr4-122896930-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001361665.2(FGF2):​c.*4534C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0971 in 152,086 control chromosomes in the GnomAD database, including 888 homozygotes. 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: 𝑓 0.097 (888 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FGF2 NM_001361665.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101

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]

NUDT6 (HGNC:8053): (nudix hydrolase 6) This gene overlaps and lies on the opposite strand from FGF2 gene, and is thought to be the FGF2 antisense gene. The two genes are independently transcribed, and their expression shows an inverse relationship, suggesting that this antisense transcript may regulate FGF2 expression. This gene has also been shown to have hormone-regulatory and antiproliferative actions in the pituitary that are independent of FGF2 expression. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF2	NM_001361665.2	c.*4534C>G		3_prime_UTR_variant	3/3	ENST00000644866.2
NUDT6	NM_007083.5	c.553+694G>C		intron_variant		ENST00000304430.10
FGF2	NM_002006.6	c.*4534C>G		3_prime_UTR_variant	3/3
NUDT6	NM_198041.3	c.46+694G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF2	ENST00000644866.2	c.*4534C>G		3_prime_UTR_variant	3/3		NM_001361665.2	P1
NUDT6	ENST00000304430.10	c.553+694G>C		intron_variant		1	NM_007083.5	P1

Frequencies

GnomAD3 genomes AF: 0.0972 AC: 14768 AN: 151968 Hom.: 887 Cov.: 32

Gnomad AFR AF: 0.0467

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0772

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0851

Gnomad FIN AF: 0.0996

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.111

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0971 AC: 14771 AN: 152086 Hom.: 888 Cov.: 32 AF XY: 0.0935 AC XY: 6952 AN XY: 74324

Gnomad4 AFR AF: 0.0467

Gnomad4 AMR AF: 0.0771

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0850

Gnomad4 FIN AF: 0.0996

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0601 Hom.: 65

Bravo AF: 0.0941

Asia WGS AF: 0.0360 AC: 125 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.0
DANN	Benign	0.59

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: rs7683093; hg19: chr4-123818085;