8-38418315-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP2PP3

The NM_023110.3(FGFR1):c.1343G>A(p.Arg448Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,614,114 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 7.90

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-38418316-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant in the FGFR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4852 (below the threshold of 3.09). Trascript score misZ: 4.2642 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3 link	c.1343G>A	p.Arg448Gln	missense_variant	Exon 10 of 18	ENST00000447712.7	NP_075598.2	P11362-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFR1	ENST00000447712.7 link	c.1343G>A	p.Arg448Gln	missense_variant	Exon 10 of 18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 link	c.1337G>A	p.Arg446Gln	missense_variant	Exon 10 of 18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 link	c.1337G>A	p.Arg446Gln	missense_variant	Exon 11 of 19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 link	c.1337G>A	p.Arg446Gln	missense_variant	Exon 10 of 18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 link	c.1076G>A	p.Arg359Gln	missense_variant	Exon 9 of 17	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 link	c.1076G>A	p.Arg359Gln	missense_variant	Exon 8 of 16	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 link	c.1070G>A	p.Arg357Gln	missense_variant	Exon 9 of 17	1		ENSP00000327229.6	P11362-14
FGFR1	ENST00000487647.5 link	n.*1034G>A		non_coding_transcript_exon_variant	Exon 9 of 12	1		ENSP00000435254.1	E9PKX3
FGFR1	ENST00000487647.5 link	n.*1034G>A		3_prime_UTR_variant	Exon 9 of 12	1		ENSP00000435254.1	E9PKX3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

249508

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 20, 2018	The FGFR1 c.1343G>A; p.Arg448Gln variant (rs758138124) has been identified in a patient diagnosed with idiopathic hypogonadotropic hypogonadism, and functional studies showed that this variant reduced but did not entirely abolish the proteinâ€™s ability to bind to the transcription factor EMX1 (Kim 2010). Another variant affecting this amino acid, p.Arg448Trp, has been reported as pathogenic for GnRH deficiency (Show 2011). The p.Arg448Gln variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 0.02% (identified on 6 out of 30,782chromosomes). The arginine at position 448 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg448Gln variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Although the available evidence is suggestive of pathogenicity, the clinical significance of the p.Arg448Gln variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2025	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 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.1343G>A (p.R448Q) alteration is located in exon 10 (coding exon 9) of the FGFR1 gene. This alteration results from a G to A substitution at nucleotide position 1343, causing the arginine (R) at amino acid position 448 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Jan 06, 2025

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 448 of the FGFR1 protein (p.Arg448Gln). This variant is present in population databases (rs758138124, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FGFR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 468283). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FGFR1 protein function with a negative predictive value of 80%. 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. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

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

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.78

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

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.2

.;.;M;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.9

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

REVEL

Uncertain

0.56

Sift

Benign

0.053

T;T;T;D;T;T;D;T;D;T

Sift4G

Benign

0.14

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

Polyphen

1.0

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

Vest4

0.86

MutPred

0.29

.;.;Loss of MoRF binding (P = 0.0283);.;.;.;.;.;.;.;

MVP

0.81

MPC

0.76

ClinPred

0.81

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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