8-38429898-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

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

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.57

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 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 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, 0.983

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_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38429898-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3 link	c.142G>A	p.Gly48Ser	missense_variant	Exon 3 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.142G>A	p.Gly48Ser	missense_variant	Exon 3 of 18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 link	c.142G>A	p.Gly48Ser	missense_variant	Exon 3 of 18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 link	c.142G>A	p.Gly48Ser	missense_variant	Exon 4 of 19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 link	c.142G>A	p.Gly48Ser	missense_variant	Exon 3 of 18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 link	c.92-1463G>A		intron_variant	Intron 2 of 16	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 link	c.92-1463G>A		intron_variant	Intron 1 of 15	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 link	c.92-1463G>A		intron_variant	Intron 2 of 16	1		ENSP00000327229.6	P11362-14
FGFR1	ENST00000487647.5 link	n.92-508G>A		intron_variant	Intron 1 of 11	1		ENSP00000435254.1	E9PKX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461446

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727038

show subpopulations

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.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 12, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 18034870, 30024674, 21682876, 27896051, 23329143, 23880303, 35669683, 16882753, 24841555) -

FGFR1-related disorder

Pathogenic:1

Aug 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Oct 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.6

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

PrimateAI

Uncertain

0.65

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

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

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

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