NM_023110.3:c.1825C>T

Variant names:

• chr8-38415899-G-A
• rs121909639
• NM_023110.3:c.1825C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_023110.3(FGFR1):​c.1825C>T​(p.Arg609*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,606 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR1 NM_023110.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 1.70

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-38415899-G-A is Pathogenic according to our data. Variant chr8-38415899-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38415899-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.1825C>T	p.Arg609*	stop_gained	Exon 13 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.1825C>T	p.Arg609*	stop_gained	Exon 13 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.1819C>T	p.Arg607*	stop_gained	Exon 13 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.1819C>T	p.Arg607*	stop_gained	Exon 14 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.1819C>T	p.Arg607*	stop_gained	Exon 13 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.1558C>T	p.Arg520*	stop_gained	Exon 12 of 17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.1558C>T	p.Arg520*	stop_gained	Exon 11 of 16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.1552C>T	p.Arg518*	stop_gained	Exon 12 of 17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*1516C>T		downstream_gene_variant		1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461606 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727122

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:3

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2023

Reproductive Endocrine Unit, Massachusetts General Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The variant NM_023110.2:c.1825C>T, p.(Arg609*) het has been classified as P1c based on the variant meeting the following ACMG Criteria: PVS1,PM2,PP3. -

Apr 28, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 08, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R609X nonsense variant in the FGFR1 gene has been reported previously inassociation with Kallmann syndrome (Riley et al., 2007; Marcos et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. Therefore, we consider the R609X variant to be pathogenic. -

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1

Jul 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16296). This premature translational stop signal has been observed in individual(s) with clinical features of Kallmann syndrome (PMID: 17360555). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg609*) in the FGFR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FGFR1 are known to be pathogenic (PMID: 12627230). -

Hypogonadotropic hypogonadism 2 with anosmia Other:1

Mar 13, 2007

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.98
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909639; hg19: chr8-38273417; COSMIC: COSV105885753; COSMIC: COSV105885753;