NM_023110.3:c.1604_1606delTGA

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_023110.3(FGFR1):c.1604_1606delTGA(p.Met535del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.31

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 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;

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 rank	MANE	Protein	UniProt
FGFR1	NM_023110.3 link	c.1604_1606delTGA	p.Met535del	disruptive_inframe_deletion	Exon 12 of 18	ENST00000447712.7	NP_075598.2	P11362-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFR1	ENST00000447712.7 link	c.1604_1606delTGA	p.Met535del	disruptive_inframe_deletion	Exon 12 of 18	1	NM_023110.3	ENSP00000400162.2	P11362-1
FGFR1	ENST00000397091.9 link	c.1598_1600delTGA	p.Met533del	disruptive_inframe_deletion	Exon 12 of 18	1		ENSP00000380280.5	P11362-7
FGFR1	ENST00000397108.8 link	c.1598_1600delTGA	p.Met533del	disruptive_inframe_deletion	Exon 13 of 19	1		ENSP00000380297.4	P11362-7
FGFR1	ENST00000397113.6 link	c.1598_1600delTGA	p.Met533del	disruptive_inframe_deletion	Exon 12 of 18	2		ENSP00000380302.2	P11362-7
FGFR1	ENST00000356207.9 link	c.1337_1339delTGA	p.Met446del	disruptive_inframe_deletion	Exon 11 of 17	1		ENSP00000348537.5	P11362-3
FGFR1	ENST00000397103.5 link	c.1337_1339delTGA	p.Met446del	disruptive_inframe_deletion	Exon 10 of 16	5		ENSP00000380292.1	E7EU09
FGFR1	ENST00000326324.10 link	c.1331_1333delTGA	p.Met444del	disruptive_inframe_deletion	Exon 11 of 17	1		ENSP00000327229.6	P11362-14
FGFR1	ENST00000487647.5 link	n.1295_1297delTGA		non_coding_transcript_exon_variant	Exon 11 of 12	1		ENSP00000435254.1	E9PKX3
FGFR1	ENST00000487647.5 link	n.1295_1297delTGA		3_prime_UTR_variant	Exon 11 of 12	1		ENSP00000435254.1	E9PKX3

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Sep 18, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 09, 2018

Muenke lab, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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

Name

Calibrated prediction

Score

Prediction

Splicing