8-38414892-G-A

Position:

• chr8-38414892-G-A

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.1864C>T​(p.Arg622Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 1.47

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 8-38414892-G-A is Pathogenic according to our data. Variant chr8-38414892-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38414892-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.1864C>T	p.Arg622Ter	stop_gained	14/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.1864C>T	p.Arg622Ter	stop_gained	14/18	1	NM_023110.3	ENSP00000400162	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	research	Reproductive Endocrine Unit, Massachusetts General Hospital	May 04, 2023	The variant NM_023110.2:c.1864C>T, p.(Arg622*) het has been classified as P1c based on the variant meeting the following ACMG Criteria: PVS1,PM2,PP3. -
risk factor, no assertion criteria provided	literature only	OMIM	Mar 01, 2007	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Chan Lab, Boston Children's Hospital

Nov 01, 2014

- -

Delayed puberty Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Chan Lab, Boston Children's Hospital

Nov 01, 2014

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Feb 12, 2021

ACMG categories: PVS1,PM2,PP3,PP5 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2018

The R622X nonsense variant has been reported previously in association with FGFR1-related disorders (Dodé et al., 2003; Pitteloud et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2023

This sequence change creates a premature translational stop signal (p.Arg622*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal dominant FGFR1-related conditions (PMID: 12627230, 17200176, 25636053, 32853167, 33548149). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16282). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
Vest4		0.98
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs121909628; hg19: chr8-38272410;