8-38417975-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP3

The NM_023110.3(FGFR1):​c.1447C>A​(p.Pro483Thr) variant causes a missense change involving the alteration of a 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P483S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FGFR1
NM_023110.3 missense

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 8.01
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain Protein kinase (size 289) in uniprot entity FGFR1_HUMAN there are 78 pathogenic changes around while only 2 benign (98%) in NM_023110.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr8-38417975-G-A is described in Lovd as [Pathogenic].
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, 0.786

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGFR1NM_023110.3 linkc.1447C>A p.Pro483Thr missense_variant Exon 11 of 18 ENST00000447712.7 NP_075598.2 P11362-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGFR1ENST00000447712.7 linkc.1447C>A p.Pro483Thr missense_variant Exon 11 of 18 1 NM_023110.3 ENSP00000400162.2 P11362-1
FGFR1ENST00000397091.9 linkc.1441C>A p.Pro481Thr missense_variant Exon 11 of 18 1 ENSP00000380280.5 P11362-7
FGFR1ENST00000397108.8 linkc.1441C>A p.Pro481Thr missense_variant Exon 12 of 19 1 ENSP00000380297.4 P11362-7
FGFR1ENST00000397113.6 linkc.1441C>A p.Pro481Thr missense_variant Exon 11 of 18 2 ENSP00000380302.2 P11362-7
FGFR1ENST00000356207.9 linkc.1180C>A p.Pro394Thr missense_variant Exon 10 of 17 1 ENSP00000348537.5 P11362-3
FGFR1ENST00000397103.5 linkc.1180C>A p.Pro394Thr missense_variant Exon 9 of 16 5 ENSP00000380292.1 E7EU09
FGFR1ENST00000326324.10 linkc.1174C>A p.Pro392Thr missense_variant Exon 10 of 17 1 ENSP00000327229.6 P11362-14
FGFR1ENST00000487647.5 linkn.*1138C>A non_coding_transcript_exon_variant Exon 10 of 12 1 ENSP00000435254.1 E9PKX3
FGFR1ENST00000487647.5 linkn.*1138C>A 3_prime_UTR_variant Exon 10 of 12 1 ENSP00000435254.1 E9PKX3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Uncertain:1
May 04, 2023
Reproductive Endocrine Unit, Massachusetts General Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

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

Hypogonadotropic hypogonadism 2 with anosmia Other:1
May 02, 2013
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
Uncertain
0.51
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
.;.;D;.;.;.;.;.;D;.
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.79
T;.;T;T;.;T;T;T;T;T
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.79
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.14
D
MutationAssessor
Benign
-0.060
.;.;N;.;.;.;.;.;.;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-6.7
D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;T;D
Sift4G
Benign
0.64
T;T;T;T;T;T;T;T;T;T
Polyphen
1.0
.;.;D;D;.;.;D;D;.;.
Vest4
0.77
MutPred
0.46
.;.;Loss of ubiquitination at K482 (P = 0.0768);.;.;.;.;.;.;.;
MVP
0.85
MPC
0.76
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.87
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs397515444; hg19: chr8-38275493; API