rs1476217

Positions:

• chr4-122897356-A-C
• chr4-122897356-A-G
• chr4-122897356-A-T

Variant summary

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

The NM_001361665.2(FGF2):​c.*4960A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 406,886 control chromosomes in the GnomAD database, including 35,738 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 0.42 (14021 hom., cov: 32)
  • Exomes 𝑓: 0.40 (21717 hom.)
• Consequence: FGF2 NM_001361665.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130

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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.*4960A>C		3_prime_UTR_variant	3/3	ENST00000644866.2	NP_001348594.1
NUDT6	NM_007083.5	c.553+268T>G		intron_variant		ENST00000304430.10	NP_009014.2
FGF2	NM_002006.6	c.*4960A>C		3_prime_UTR_variant	3/3		NP_001997.5
NUDT6	NM_198041.3	c.46+268T>G		intron_variant			NP_932158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000644866.2	c.*4960A>C		3_prime_UTR_variant	3/3		NM_001361665.2	ENSP00000494222	P1
NUDT6	ENST00000304430.10	c.553+268T>G		intron_variant		1	NM_007083.5	ENSP00000306070	P1

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63857 AN: 151828 Hom.: 14003 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.399

GnomAD4 exome AF: 0.399 AC: 101779 AN: 254940 Hom.: 21717 Cov.: 0 AF XY: 0.411 AC XY: 55201 AN XY: 134448

Gnomad4 AFR exome AF: 0.548

Gnomad4 AMR exome AF: 0.330

Gnomad4 ASJ exome AF: 0.411

Gnomad4 EAS exome AF: 0.486

Gnomad4 SAS exome AF: 0.615

Gnomad4 FIN exome AF: 0.322

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.386

GnomAD4 genome AF: 0.421 AC: 63931 AN: 151946 Hom.: 14021 Cov.: 32 AF XY: 0.423 AC XY: 31436 AN XY: 74260

Gnomad4 AFR AF: 0.539

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.615

Gnomad4 FIN AF: 0.327

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.399

Alfa AF: 0.339 Hom.: 2559

Bravo AF: 0.419

Asia WGS AF: 0.505 AC: 1748 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.65

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: rs1476217; hg19: chr4-123818511;