rs397515481

Positions:

• chr8-38428048-A-C
• chr8-38428048-A-G
• chr8-38428048-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_023110.3(FGFR1):​c.494T>G​(p.Leu165Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L165S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Heparin-binding (size 17) in uniprot entity FGFR1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 chr8-38428048-A-G is described in Lovd as [Pathogenic].
• 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, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.494T>G	p.Leu165Trp	missense_variant	5/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.494T>G	p.Leu165Trp	missense_variant	5/18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.488T>G	p.Leu163Trp	missense_variant	5/18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.488T>G	p.Leu163Trp	missense_variant	6/19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.488T>G	p.Leu163Trp	missense_variant	5/18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.227T>G	p.Leu76Trp	missense_variant	4/17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.221T>G	p.Leu74Trp	missense_variant	3/16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.221T>G	p.Leu74Trp	missense_variant	4/17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*185T>G		non_coding_transcript_exon_variant	4/12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*185T>G		3_prime_UTR_variant	4/12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.94	.;.;D;D;.;.;.;.;.;.;T;.;T;T;.;T;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.4	.;.;M;.;.;M;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;.;.;.;D;.
Polyphen		1.0	D;D;D;D;.;D;D;D;D;D;.;D;.;.;.;.;.
Vest4		0.66
MutPred		0.71		.;.;Gain of MoRF binding (P = 0.0217);.;.;Gain of MoRF binding (P = 0.0217);.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0217);.;.;.;
MVP		0.93
MPC		3.3
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-38285566; COSMIC: COSV58346501; COSMIC: COSV58346501;