5-142595357-C-G

Position:

chr5-142595357-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_000800.5(FGF1):c.401G>C(p.Arg134Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

FGF1
NM_000800.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.295

Variant links:

Genes affected

FGF1 (HGNC:3665): (fibroblast growth factor 1) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This protein functions as a modifier of endothelial cell migration and proliferation, as well as an angiogenic factor. It acts as a mitogen for a variety of mesoderm- and neuroectoderm-derived cells in vitro, thus is thought to be involved in organogenesis. Multiple alternatively spliced variants encoding different isoforms have been described. [provided by RefSeq, Jan 2009]

FGF1 links:

SPRY4-AS1 (HGNC:53465): (SPRY4 antisense RNA 1)

SPRY4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a mutagenesis_site Reduced integrin-binding; when associated with E-133. Defective in integrin-, heparin- and FGFR1-binding, and defective in inducing FGF1 signaling, cell proliferation and cell migration; when associated with E-127; E-128 and E-133. (size 0) in uniprot entity FGF1_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.25785303).

BS2

High AC in GnomAdExome4 at 125 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGF1	NM_000800.5 linkuse as main transcript	c.401G>C	p.Arg134Pro	missense_variant	4/4	ENST00000337706.7	NP_000791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGF1	ENST00000337706.7 linkuse as main transcript	c.401G>C	p.Arg134Pro	missense_variant	4/4	2	NM_000800.5	ENSP00000338548	P1	P05230-1
SPRY4-AS1	ENST00000443800.5 linkuse as main transcript	n.356+13443C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

250972

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000971

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000855

AC:

125

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.000108

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.401G>C (p.R134P) alteration is located in exon 5 (coding exon 3) of the FGF1 gene. This alteration results from a G to C substitution at nucleotide position 401, causing the arginine (R) at amino acid position 134 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.56

D;D;D;D;D;D;D;D;D

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.85

.;.;.;D;.;.;.;.;.

M_CAP

Benign

0.068

MetaRNN

Benign

0.26

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.39

N;N;N;N;N;N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.50

N;.;.;.;.;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.27

T;.;.;.;.;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;B;B;B;B

Vest4

0.24

MutPred

0.55

Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);

MVP

0.90

MPC

0.24

ClinPred

0.042

GERP RS

1.9

Varity_R

0.79

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over