8-38421853-A-T

Position:

• chr8-38421853-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_023110.3(FGFR1):​c.1025T>A​(p.Leu342*) variant causes a stop gained 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.1025T>A	p.Leu342*	stop_gained	8/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.1025T>A	p.Leu342*	stop_gained	8/18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.1019T>A	p.Leu340*	stop_gained	8/18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.1019T>A	p.Leu340*	stop_gained	9/19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.1019T>A	p.Leu340*	stop_gained	8/18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.758T>A	p.Leu253*	stop_gained	7/17	1		ENSP00000348537.5
FGFR1	ENST00000326324.10	c.752T>A	p.Leu251*	stop_gained	7/17	1		ENSP00000327229.6
FGFR1	ENST00000397103.5	c.814+1172T>A		intron_variant		5		ENSP00000380292.1
FGFR1	ENST00000487647.5	n.*716T>A		non_coding_transcript_exon_variant	7/12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*716T>A		3_prime_UTR_variant	7/12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.99
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-38279371;