4-122896919-T-C

Variant names:

• chr4-122896919-T-C
• rs3747676
• NM_001361665.2:c.*4523T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001361665.2(FGF2):​c.*4523T>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 0.429 in 152,116 control chromosomes in the GnomAD database, including 16,917 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 0.43 (16917 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: FGF2 NM_001361665.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.446
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF2	NM_001361665.2	c.*4523T>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000644866.2	NP_001348594.1
NUDT6	NM_007083.5	c.553+705A>G		intron_variant	Intron 4 of 4	ENST00000304430.10	NP_009014.2
FGF2	NM_002006.6	c.*4523T>C		3_prime_UTR_variant	Exon 3 of 3		NP_001997.5
NUDT6	NM_198041.3	c.46+705A>G		intron_variant	Intron 4 of 4		NP_932158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF2	ENST00000644866.2	c.*4523T>C		3_prime_UTR_variant	Exon 3 of 3		NM_001361665.2	ENSP00000494222.1
NUDT6	ENST00000304430.10	c.553+705A>G		intron_variant	Intron 4 of 4	1	NM_007083.5	ENSP00000306070.5

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65223 AN: 151996 Hom.: 16913 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.454

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.429 AC: 65235 AN: 152114 Hom.: 16917 Cov.: 32 AF XY: 0.426 AC XY: 31692 AN XY: 74338

African (AFR) AF: 0.125 AC: 5204 AN: 41554

American (AMR) AF: 0.493 AC: 7537 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1637 AN: 3470

East Asian (EAS) AF: 0.494 AC: 2549 AN: 5158

South Asian (SAS) AF: 0.299 AC: 1441 AN: 4816

European-Finnish (FIN) AF: 0.598 AC: 6313 AN: 10556

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.573 AC: 38944 AN: 67968

Other (OTH) AF: 0.455 AC: 962 AN: 2112

Alfa AF: 0.535 Hom.: 22444

Bravo AF: 0.414

Asia WGS AF: 0.418 AC: 1446 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.1
DANN	Benign	0.61
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3747676; hg19: chr4-123818074;