rs41348645

Positions:

• chr4-122894208-G-A

Variant summary

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

The NM_001361665.2(FGF2):​c.*1812G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 152,078 control chromosomes in the GnomAD database, including 18,483 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 0.47 (18483 hom., cov: 33)
  • Exomes 𝑓: 0.25 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FGF2 NM_001361665.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.415

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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.*1812G>A		3_prime_UTR_variant	3/3	ENST00000644866.2	NP_001348594.1
NUDT6	NM_007083.5	c.554-983C>T		intron_variant		ENST00000304430.10	NP_009014.2
FGF2	NM_002006.6	c.*1812G>A		3_prime_UTR_variant	3/3		NP_001997.5
NUDT6	NM_198041.3	c.47-983C>T		intron_variant			NP_932158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000644866.2	c.*1812G>A		3_prime_UTR_variant	3/3		NM_001361665.2	ENSP00000494222.1
NUDT6	ENST00000304430.10	c.554-983C>T		intron_variant		1	NM_007083.5	ENSP00000306070.5

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71724 AN: 151958 Hom.: 18450 Cov.: 33

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.441

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.472 AC: 71815 AN: 152078 Hom.: 18483 Cov.: 33 AF XY: 0.473 AC XY: 35195 AN XY: 74348

Gnomad4 AFR AF: 0.687

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.448

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.616

Gnomad4 FIN AF: 0.331

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.441

Alfa AF: 0.449 Hom.: 2422

Bravo AF: 0.477

Asia WGS AF: 0.516 AC: 1793 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.73

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: rs41348645; hg19: chr4-123815363;