chr8-38429898-C-T

Position:

• chr8-38429898-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_023110.3(FGFR1):​c.142G>A​(p.Gly48Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,446 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.57

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain Ig-like C2-type 1 (size 94) in uniprot entity FGFR1_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) in NM_023110.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.983
• PP5: Variant 8-38429898-C-T is Pathogenic according to our data. Variant chr8-38429898-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16298.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-38429898-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.142G>A	p.Gly48Ser	missense_variant	3/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.142G>A	p.Gly48Ser	missense_variant	3/18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.142G>A	p.Gly48Ser	missense_variant	3/18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.142G>A	p.Gly48Ser	missense_variant	4/19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.142G>A	p.Gly48Ser	missense_variant	3/18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.92-1463G>A		intron_variant		1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.92-1463G>A		intron_variant		5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.92-1463G>A		intron_variant		1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.92-508G>A		intron_variant		1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461446 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

FGFR1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2024

The FGFR1 c.142G>A variant is predicted to result in the amino acid substitution p.Gly48Ser. This variant has been reported in individuals with hypogonadotropic hypogonadism with or without anosmia (Trarbach et al. 2006. PubMed ID: 16882753; Laitinen et al. 2011. PubMed ID: 21682876; Hero M et al 2014. PubMed ID: 24841555 ). In vitro functional studies showed that this variant displayed impaired downstream signaling as assessed by MAPK phosphorylation (Laitinen et al. 2011. PubMed ID: 21682876). An alternate nucleotide change affecting the same amino acid (c.142G>C; p.Gly48Arg) has also been reported in an individual with hypogonadotropic hypogonadism (Xie et al. 2022. PubMed ID: 35729303). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2006

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

FGFR1: PM2, PS4:Moderate, PM5:Supporting, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;D;.;.;.;.;.;T;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.6	.;M;M;.;M;M;.;M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;.;.
Polyphen		1.0	D;D;D;.;D;D;D;D;.;.
Vest4		0.86
MutPred		0.90		.;Loss of catalytic residue at G48 (P = 0.2117);Loss of catalytic residue at G48 (P = 0.2117);Loss of catalytic residue at G48 (P = 0.2117);Loss of catalytic residue at G48 (P = 0.2117);Loss of catalytic residue at G48 (P = 0.2117);.;Loss of catalytic residue at G48 (P = 0.2117);Loss of catalytic residue at G48 (P = 0.2117);Loss of catalytic residue at G48 (P = 0.2117);
MVP		0.93
MPC		0.23
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909640; hg19: chr8-38287416;