8-38418227-C-T

Variant names:

• chr8-38418227-C-T
• rs1554552774
• NM_023110.3:c.1430+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_023110.3(FGFR1):​c.1430+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.60

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-38418227-C-T is Pathogenic according to our data. Variant chr8-38418227-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 463529.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-38418227-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.1430+1G>A		splice_donor_variant, intron_variant	Intron 10 of 17	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.1430+1G>A		splice_donor_variant, intron_variant	Intron 10 of 17	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.1424+1G>A		splice_donor_variant, intron_variant	Intron 10 of 17	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.1424+1G>A		splice_donor_variant, intron_variant	Intron 11 of 18	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.1424+1G>A		splice_donor_variant, intron_variant	Intron 10 of 17	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.1163+1G>A		splice_donor_variant, intron_variant	Intron 9 of 16	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.1163+1G>A		splice_donor_variant, intron_variant	Intron 8 of 15	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.1157+1G>A		splice_donor_variant, intron_variant	Intron 9 of 16	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*1121+1G>A		splice_donor_variant, intron_variant	Intron 9 of 11	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pfeiffer syndrome;C1563720:Hypogonadotropic hypogonadism 2 with or without anosmia Pathogenic:1

Sep 07, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FGFR1 are known to be pathogenic (PMID: 12627230). Family studies have indicated that this variant was not present in the parents of an individual with features consistent with an FGFR1-related disease, which suggests that it was de novo in that affected individual (Invitae). This variant has not been reported in the literature in individuals with FGFR1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 10 of the FGFR1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554552774; hg19: chr8-38275745;