rs1554551657

chr8-38417362-TTCA-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_023110.3(FGFR1):c.1604_1606del(p.Met535del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.31

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 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_023110.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_023110.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 8-38417362-TTCA-T is Pathogenic according to our data. Variant chr8-38417362-TTCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR1	NM_023110.3	c.1604_1606del	p.Met535del	inframe_deletion	12/18	ENST00000447712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR1	ENST00000447712.7	c.1604_1606del	p.Met535del	inframe_deletion	12/18	1	NM_023110.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2017

The c.1604_1606delTGA variant in the FGFR1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes an in-frame deletion of codon Methionine 535, denoted p.Met535del. The c.1604_1606delTGA variant is not observed in large population cohorts (Lek et al., 2016). The deleted amino acid is a residue that is conserved across species and within the protein kinase domain. In silico analysis predicts that deletion of this variant is probably damaging to the protein structure/function. We interpret c.1604_1606delTGA as a likely pathogenic variant. -

Hartsfield-Bixler-Demyer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muenke lab, National Institutes of Health

Mar 09, 2018

Known disease association; ACMG criteria are met:PM1/PM2/PM4/PM5;PP3. Kinase domain; interferes with kinase activity of receptor dimers in zebrafish. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1554551657; hg19: chr8-38274880;