8-38413783-G-T

Position:

chr8-38413783-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_023110.3(FGFR1):c.2314C>A(p.Pro772Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P772S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FGFR1
NM_023110.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.90

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:

FGFR1 (HGNC:):

FGFR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.31080383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3 linkuse as main transcript	c.2314C>A	p.Pro772Thr	missense_variant	18/18	ENST00000447712.7	NP_075598.2	P11362-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FGFR1	ENST00000447712.7 linkuse as main transcript	c.2314C>A	p.Pro772Thr	missense_variant	18/18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 linkuse as main transcript	c.2308C>A	p.Pro770Thr	missense_variant	18/18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 linkuse as main transcript	c.2308C>A	p.Pro770Thr	missense_variant	19/19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 linkuse as main transcript	c.2308C>A	p.Pro770Thr	missense_variant	18/18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 linkuse as main transcript	c.2047C>A	p.Pro683Thr	missense_variant	17/17	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 linkuse as main transcript	c.2047C>A	p.Pro683Thr	missense_variant	16/16	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 linkuse as main transcript	c.2041C>A	p.Pro681Thr	missense_variant	17/17	1		ENSP00000327229.6	P11362-14

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249124

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135210

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2022

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; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

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

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.31

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.1

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

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.1

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

REVEL

Uncertain

0.57

Sift

Benign

0.15

T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.094

T;T;T;T;T;T;T;T;T;T

Polyphen

0.96, 0.98, 0.94

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

Vest4

0.45

MutPred

0.30

.;.;Gain of glycosylation at P772 (P = 0.0701);.;.;.;.;.;.;.;

MVP

0.83

MPC

2.0

ClinPred

0.96

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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