rs121913473

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The ENST00000447712.7(FGFR1):c.374C>T(p.Ser125Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S125S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

FGFR1
ENST00000447712.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.19

Variant links:

Genes affected

FGFR1 (HGNC:3688): (fibroblast growth factor receptor 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction. Mutations in this gene have been associated with Pfeiffer syndrome, Jackson-Weiss syndrome, Antley-Bixler syndrome, osteoglophonic dysplasia, and autosomal dominant Kallmann syndrome 2. Chromosomal aberrations involving this gene are associated with stem cell myeloproliferative disorder and stem cell leukemia lymphoma syndrome. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

FGFR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR1. . Gene score misZ 2.4852 (greater than the threshold 3.09). Trascript score misZ 4.2642 (greater than threshold 3.09). GenCC has associacion of gene with hypogonadotropic hypogonadism 2 with or without anosmia, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism, tooth agenesis, isolated trigonocephaly, Pfeiffer syndrome type 1, Jackson-Weiss syndrome, Pfeiffer syndrome, Kallmann syndrome, septooptic dysplasia, hypogonadotropic hypogonadism 7 with or without anosmia, holoprosencephaly, osteoglophonic dwarfism, Hartsfield-Bixler-Demyer syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.4134978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3 linkuse as main transcript	c.374C>T	p.Ser125Leu	missense_variant	4/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7 linkuse as main transcript	c.374C>T	p.Ser125Leu	missense_variant	4/18	1	NM_023110.3	ENSP00000400162	P4	P11362-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

245296

Hom.:

AF XY:

0.00000750

AC XY:

AN XY:

133350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000562

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1460564

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726534

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Reproductive Endocrine Unit, Massachusetts General Hospital

May 04, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27896051, 25157968, 17344846, 33081025, 33268819) -

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR1 protein function. ClinVar contains an entry for this variant (Variation ID: 376297). This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. This variant is present in population databases (rs121913473, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 125 of the FGFR1 protein (p.Ser125Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;.;D;T;.;.;.;.;.;.;T;.;T;.;T;D;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.41

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

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.69

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.8

D;D;D;.;D;D;D;N;D;N;D;D;D;D;D;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.044

D;T;D;.;T;D;T;T;D;T;D;T;D;D;D;D;D

Sift4G

Benign

0.31

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

Polyphen

0.49

P;B;B;B;.;B;B;B;B;B;.;B;.;.;.;.;.

Vest4

0.43

MVP

0.71

MPC

0.034

ClinPred

0.63

GERP RS

5.7

Varity_R

0.24

gMVP

0.39

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