rs121909641

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

The NM_023110.3(FGFR1):c.1097C>T(p.Pro366Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,828 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1O:1

Conservation

PhyloP100: 5.82

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 Uncertain_significance. Variant got 5 ACMG points.

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, 0.755

PP5

Variant 8-38419720-G-A is Pathogenic according to our data. Variant chr8-38419720-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16299.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}. Variant chr8-38419720-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3 link	c.1097C>T	p.Pro366Leu	missense_variant	Exon 9 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.1097C>T	p.Pro366Leu	missense_variant	Exon 9 of 18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 link	c.1091C>T	p.Pro364Leu	missense_variant	Exon 9 of 18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 link	c.1091C>T	p.Pro364Leu	missense_variant	Exon 10 of 19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 link	c.1091C>T	p.Pro364Leu	missense_variant	Exon 9 of 18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 link	c.830C>T	p.Pro277Leu	missense_variant	Exon 8 of 17	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 link	c.830C>T	p.Pro277Leu	missense_variant	Exon 7 of 16	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 link	c.824C>T	p.Pro275Leu	missense_variant	Exon 8 of 17	1		ENSP00000327229.6	P11362-14
FGFR1	ENST00000487647.5 link	n.*788C>T		non_coding_transcript_exon_variant	Exon 8 of 12	1		ENSP00000435254.1	E9PKX3
FGFR1	ENST00000487647.5 link	n.*788C>T		3_prime_UTR_variant	Exon 8 of 12	1		ENSP00000435254.1	E9PKX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727210

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 7 with or without anosmia

Pathogenic:1

Nov 01, 2014

Chan Lab, Boston Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

Hypogonadotropic hypogonadism 2 with or without anosmia

Pathogenic:1

May 04, 2023

Reproductive Endocrine Unit, Massachusetts General Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The variant has been classified as LP2 based on the variant meeting the following ACMG Criteria: PS2,PM2. -

Pfeiffer syndrome;C0406612:Encephalocraniocutaneous lipomatosis;C0432122:Trigonocephaly 1;C0432283:Osteoglophonic dysplasia;C0795998:Jackson-Weiss syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia;C1845146:Hartsfield-Bixler-Demyer syndrome

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Jan 20, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in other patients with isolated gonadotropin-releasing hormone deficiency or idiopathic hypogonadotropic hypogonadism in published literature; however, detailed information is not available and one patient harbored variants in other genes (Zhu J et al., 2015; Stamou M et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Beneduzzi[article], 31628846, 25636053, 16882753, 23329143) -

Hypogonadotropic hypogonadism 2 with anosmia

Other:1

Oct 01, 2006

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

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

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

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

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

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.75

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

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.5

.;.;L;L;.;.;.;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.033

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

Sift4G

Uncertain

0.043

D;D;T;D;D;T;D;T;D;D

Polyphen

0.98

D;D;P;P;D;P;P;P;.;D

Vest4

0.82

MutPred

0.53

.;.;Loss of disorder (P = 0.0276);Loss of disorder (P = 0.0276);.;.;.;.;.;.;

MVP

0.93

MPC

0.42

ClinPred

0.81

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.80

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

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

Other links and lift over