8-38427942-G-C

Position:

• chr8-38427942-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_023110.3(FGFR1):​c.600C>G​(p.Asp200Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D200D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.180

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Ig-like C2-type 2 (size 88) in uniprot entity FGFR1_HUMAN there are 29 pathogenic changes around while only 1 benign (97%) in NM_023110.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR1. . Gene score misZ 2.4852 (greater than the threshold 3.09). Trascript score misZ 4.2642 (greater than threshold 3.09). GenCC has associacion of gene with hypogonadotropic hypogonadism 2 with or without anosmia, encephalocraniocutaneous lipomatosis, hypogonadotropic hypogonadism, tooth agenesis, isolated trigonocephaly, Pfeiffer syndrome type 1, Jackson-Weiss syndrome, Pfeiffer syndrome, Kallmann syndrome, septooptic dysplasia, hypogonadotropic hypogonadism 7 with or without anosmia, holoprosencephaly, osteoglophonic dwarfism, Hartsfield-Bixler-Demyer syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14429674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.600C>G	p.Asp200Glu	missense_variant	5/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.600C>G	p.Asp200Glu	missense_variant	5/18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.594C>G	p.Asp198Glu	missense_variant	5/18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.594C>G	p.Asp198Glu	missense_variant	6/19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.594C>G	p.Asp198Glu	missense_variant	5/18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.333C>G	p.Asp111Glu	missense_variant	4/17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.327C>G	p.Asp109Glu	missense_variant	3/16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.327C>G	p.Asp109Glu	missense_variant	4/17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*291C>G		non_coding_transcript_exon_variant	4/12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*291C>G		3_prime_UTR_variant	4/12	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
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Benign	0.32	.;.;T;T;.;.;.;.;.;.;T;.;T;T;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.63	T;.;T;T;T;T;.;D;T;D;D;T;D;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.51	.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	1.2	N;N;N;.;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;T
Polyphen		0.058	B;B;B;B;.;B;B;B;B;B;.;B;.;.;.;.
Vest4		0.066
MutPred		0.47		.;.;Gain of methylation at K198 (P = 0.0708);.;.;Gain of methylation at K198 (P = 0.0708);.;.;.;.;.;.;.;Gain of methylation at K198 (P = 0.0708);.;.;
MVP		0.60
MPC		1.3
ClinPred		0.66	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-38285460;