chr8-38417975-G-A

Position:

chr8-38417975-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP3

The NM_023110.3(FGFR1):c.1447C>T(p.Pro483Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P483T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.01

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:

FGFR1 (HGNC:):

FGFR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a domain Protein kinase (size 289) in uniprot entity FGFR1_HUMAN there are 78 pathogenic changes around while only 2 benign (98%) in NM_023110.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-38417975-G-T is described in Lovd as [Likely_pathogenic].

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3 linkuse as main transcript	c.1447C>T	p.Pro483Ser	missense_variant	11/18	ENST00000447712.7	NP_075598.2	P11362-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FGFR1	ENST00000447712.7 linkuse as main transcript	c.1447C>T	p.Pro483Ser	missense_variant	11/18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 linkuse as main transcript	c.1441C>T	p.Pro481Ser	missense_variant	11/18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 linkuse as main transcript	c.1441C>T	p.Pro481Ser	missense_variant	12/19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 linkuse as main transcript	c.1441C>T	p.Pro481Ser	missense_variant	11/18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 linkuse as main transcript	c.1180C>T	p.Pro394Ser	missense_variant	10/17	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 linkuse as main transcript	c.1180C>T	p.Pro394Ser	missense_variant	9/16	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 linkuse as main transcript	c.1174C>T	p.Pro392Ser	missense_variant	10/17	1		ENSP00000327229.6	P11362-14
FGFR1	ENST00000487647.5 linkuse as main transcript	n.*1138C>T		non_coding_transcript_exon_variant	10/12	1		ENSP00000435254.1	E9PKX3
FGFR1	ENST00000487647.5 linkuse as main transcript	n.*1138C>T		3_prime_UTR_variant	10/12	1		ENSP00000435254.1	E9PKX3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

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:

0.00000401

AC:

AN:

249568

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135400

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

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:

0.0000307

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pfeiffer syndrome;C0406612:Encephalocraniocutaneous lipomatosis;C0432122:Trigonocephaly 1;C0432283:Osteoglophonic dysplasia;C0795998:Jackson-Weiss syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia;C1845146:Hartsfield-Bixler-Demyer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 26, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22319038, 25759380) -

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

Jun 15, 2023

ClinVar contains an entry for this variant (Variation ID: 1187468). This missense change has been observed in individual(s) with FGFR1-related conditions (PMID: 22319038). This variant is present in population databases (rs397515444, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 483 of the FGFR1 protein (p.Pro483Ser). 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. 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. Experimental studies have shown that this missense change affects FGFR1 function (PMID: 22319038). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

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

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.82

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

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

0.71

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

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.7

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

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

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

Sift4G

Benign

0.33

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

Polyphen

1.0

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

Vest4

0.85

MutPred

0.45

.;.;Gain of phosphorylation at P483 (P = 0.1023);.;.;.;.;.;.;.;

MVP

0.90

MPC

0.73

ClinPred

0.97

GERP RS

5.6

Varity_R

0.86

gMVP

0.60

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