8-38414166-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_023110.3(FGFR1):c.2172C>G(p.Asn724Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.93

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_023110.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FGFR1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-38414166-G-C is Pathogenic according to our data. Variant chr8-38414166-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242708.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR1	NM_023110.3	c.2172C>G	p.Asn724Lys	missense_variant	16/18	ENST00000447712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR1	ENST00000447712.7	c.2172C>G	p.Asn724Lys	missense_variant	16/18	1	NM_023110.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Reproductive Endocrine Unit, Massachusetts General Hospital

May 04, 2023

The variant has been classified as LP2 based on the variant meeting the following ACMG Criteria: PS3,PM2,PP2. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 18, 2021

This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with clinical features of normosmic idiopathic hypogonadotropic hypogonadism (PMID: 16606836). This sequence change replaces asparagine with lysine at codon 724 of the FGFR1 protein (p.Asn724Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;.;D;D;.;D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T
Polyphen		0.73, 0.69	.;.;P;P;.;.;P;P;.;.
Vest4		0.60
MutPred		0.65		.;.;Gain of methylation at N724 (P = 7e-04);.;.;.;.;.;.;.;
MVP		0.77
MPC		1.5
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 5
DS_DL_spliceai		0.96		Position offset: -14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606806; hg19: chr8-38271684;