8-38417331-G-T

Position:

• chr8-38417331-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_023110.3(FGFR1):​c.1638C>A​(p.Asn546Lys) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 2.11

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 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
• 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). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. GenCC has associacion of the 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, 0.94
• PP5: Variant 8-38417331-G-T is Pathogenic according to our data. Variant chr8-38417331-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 224896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38417331-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.1638C>A	p.Asn546Lys	missense_variant	12/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.1638C>A	p.Asn546Lys	missense_variant	12/18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.1632C>A	p.Asn544Lys	missense_variant	12/18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.1632C>A	p.Asn544Lys	missense_variant	13/19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.1632C>A	p.Asn544Lys	missense_variant	12/18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.1371C>A	p.Asn457Lys	missense_variant	11/17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.1371C>A	p.Asn457Lys	missense_variant	10/16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.1365C>A	p.Asn455Lys	missense_variant	11/17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*1329C>A		non_coding_transcript_exon_variant	11/12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*1329C>A		3_prime_UTR_variant	11/12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalocraniocutaneous lipomatosis Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 11, 2016	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	May 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Rosette-forming glioneuronal tumor Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Donald Williams Parsons Laboratory, Baylor College of Medicine

-

- -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;D;.;.;.;.;.;D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;.;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	-0.28	.;.;N;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;.;D;D;.;.
Vest4		0.97
MutPred		0.77		.;.;Gain of methylation at N546 (P = 0.0047);.;.;.;.;.;.;.;
MVP		0.93
MPC		2.2
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.99
gMVP		0.82

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

Other links and lift over

dbSNP: rs779707422; hg19: chr8-38274849; COSMIC: COSV58329537; COSMIC: COSV58329537;