4-122876325-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001361665.2(FGF2):c.183G>T(p.Lys61Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000387 in 1,605,748 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: FGF2 NM_001361665.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.63

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010801256).
• BP6: Variant 4-122876325-G-T is Benign according to our data. Variant chr4-122876325-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 714247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGF2	NM_001361665.2	c.183G>T	p.Lys61Asn	missense_variant	2/3	ENST00000644866.2
FGF2	NM_002006.6	c.582G>T	p.Lys194Asn	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGF2	ENST00000644866.2	c.183G>T	p.Lys61Asn	missense_variant	2/3		NM_001361665.2	P1
FGF2	ENST00000264498.9	c.582G>T	p.Lys194Asn	missense_variant	2/3	1
FGF2	ENST00000608478.1	c.183G>T	p.Lys61Asn	missense_variant	2/3	1		P1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 151930 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000593 AC: 149 AN: 251428 Hom.: 1 AF XY: 0.000442 AC XY: 60 AN XY: 135888

Gnomad AFR exome AF: 0.00547

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000257 AC: 374 AN: 1453700 Hom.: 3 Cov.: 29 AF XY: 0.000229 AC XY: 166 AN XY: 723806

Gnomad4 AFR exome AF: 0.00456

Gnomad4 AMR exome AF: 0.000940

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.000549

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152048 Hom.: 1 Cov.: 32 AF XY: 0.00166 AC XY: 123 AN XY: 74310

Gnomad4 AFR AF: 0.00456

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000374 Hom.: 0

Bravo AF: 0.00177

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.063
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.92	D;D;.;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Uncertain	0.076	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.7	N;.;.;.
REVEL	Uncertain	0.49
Sift	Benign	0.050	D;.;.;.
Sift4G	Benign	0.19	T;T;T;.
Polyphen		0.97	.;D;.;.
Vest4		0.68
MutPred		0.60		Loss of ubiquitination at K194 (P = 0.0118);Loss of ubiquitination at K194 (P = 0.0118);.;.;
MVP		0.89
ClinPred		0.026	T
GERP RS		1.9
Varity_R		0.75
gMVP		0.55

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: rs148587537; hg19: chr4-123797480;