rs1554551657

Variant names:

• chr8-38417362-TTCA-T
• rs1554551657
• NM_023110.3:c.1604_1606delTGA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.31
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• encephalocraniocutaneous lipomatosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hartsfield-Bixler-Demyer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
• hypogonadotropic hypogonadism 2 with or without anosmia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteoglophonic dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Jackson-Weiss syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated trigonocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• septooptic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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	c.1604_1606delTGA	p.Met535del	disruptive_inframe_deletion	Exon 12 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.1604_1606delTGA	p.Met535del	disruptive_inframe_deletion	Exon 12 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.1598_1600delTGA	p.Met533del	disruptive_inframe_deletion	Exon 12 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.1598_1600delTGA	p.Met533del	disruptive_inframe_deletion	Exon 13 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.1598_1600delTGA	p.Met533del	disruptive_inframe_deletion	Exon 12 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.1337_1339delTGA	p.Met446del	disruptive_inframe_deletion	Exon 11 of 17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.1337_1339delTGA	p.Met446del	disruptive_inframe_deletion	Exon 10 of 16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.1331_1333delTGA	p.Met444del	disruptive_inframe_deletion	Exon 11 of 17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*1295_*1297delTGA		non_coding_transcript_exon_variant	Exon 11 of 12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*1295_*1297delTGA		3_prime_UTR_variant	Exon 11 of 12	1		ENSP00000435254.1

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

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
PhyloP100		9.3
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554551657; hg19: chr8-38274880;