Genetic Variant FGF2:c.*4720A>T (chr4-122897116-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001361665.2(FGF2):c.*4720A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 152,554 control chromosomes in the GnomAD database, including 63,452 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 0.91 ( 63283 hom., cov: 32)

Exomes 𝑓: 0.94 ( 169 hom. )

Consequence

FGF2
NM_001361665.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.158

Publications

9 publications found

Variant links:

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]

FGF2 links:

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]

NUDT6 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
FGF2	NM_001361665.2 link	c.*4720A>T	3_prime_UTR_variant	Exon 3 of 3	ENST00000644866.2	NP_001348594.1
NUDT6	NM_007083.5 link	c.553+508T>A	intron_variant	Intron 4 of 4	ENST00000304430.10	NP_009014.2
FGF2	NM_002006.6 link	c.*4720A>T	3_prime_UTR_variant	Exon 3 of 3		NP_001997.5
NUDT6	NM_198041.3 link	c.46+508T>A	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 link	c.*4720A>T		3_prime_UTR_variant	Exon 3 of 3		NM_001361665.2	ENSP00000494222.1
NUDT6	ENST00000304430.10 link	c.553+508T>A		intron_variant	Intron 4 of 4	1	NM_007083.5	ENSP00000306070.5

Frequencies

GnomAD3 genomes

AF:

0.910

AC:

138440

AN:

152058

Hom.:

63235

Cov.:

show subpopulations

Gnomad AFR

AF:

0.843

Gnomad AMI

AF:

0.998

Gnomad AMR

AF:

0.875

Gnomad ASJ

AF:

0.920

Gnomad EAS

AF:

0.959

Gnomad SAS

AF:

0.916

Gnomad FIN

AF:

0.928

Gnomad MID

AF:

0.821

Gnomad NFE

AF:

0.951

Gnomad OTH

AF:

0.903

GnomAD4 exome

AF:

0.944

AC:

357

AN:

378

Hom.:

169

Cov.:

AF XY:

0.942

AC XY:

196

AN XY:

208

show subpopulations

African (AFR)

AF:

0.750

AC:

AN:

American (AMR)

AF:

0.800

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.958

AC:

AN:

South Asian (SAS)

AF:

0.889

AC:

AN:

European-Finnish (FIN)

AF:

0.875

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.968

AC:

271

AN:

280

Other (OTH)

AF:

0.900

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.910

AC:

138548

AN:

152176

Hom.:

63283

Cov.:

AF XY:

0.909

AC XY:

67644

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.843

AC:

35022

AN:

41526

American (AMR)

AF:

0.876

AC:

13380

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.920

AC:

3192

AN:

3470

East Asian (EAS)

AF:

0.959

AC:

4979

AN:

5190

South Asian (SAS)

AF:

0.916

AC:

4411

AN:

4816

European-Finnish (FIN)

AF:

0.928

AC:

9834

AN:

10594

Middle Eastern (MID)

AF:

0.829

AC:

237

AN:

286

European-Non Finnish (NFE)

AF:

0.951

AC:

64672

AN:

67988

Other (OTH)

AF:

0.905

AC:

1911

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

632

1265

1897

2530

3162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.924

Hom.:

8081

Bravo

AF:

0.902

Asia WGS

AF:

0.940

AC:

3244

AN:

3450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

6.4

(source)

DANN

Benign

0.72

PhyloP100

0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over