8-38417975-G-T

Variant names:

• chr8-38417975-G-T
• rs397515444
• NM_023110.3:c.1447C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_023110.3(FGFR1):​c.1447C>A​(p.Pro483Thr) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P483S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 8 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-38417975-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in the FGFR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4852 (below the threshold of 3.09). Trascript score misZ: 4.2642 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.1447C>A	p.Pro483Thr	missense_variant	Exon 11 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.1447C>A	p.Pro483Thr	missense_variant	Exon 11 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.1441C>A	p.Pro481Thr	missense_variant	Exon 11 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.1441C>A	p.Pro481Thr	missense_variant	Exon 12 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.1441C>A	p.Pro481Thr	missense_variant	Exon 11 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.1180C>A	p.Pro394Thr	missense_variant	Exon 10 of 17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.1180C>A	p.Pro394Thr	missense_variant	Exon 9 of 16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.1174C>A	p.Pro392Thr	missense_variant	Exon 10 of 17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*1138C>A		non_coding_transcript_exon_variant	Exon 10 of 12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*1138C>A		3_prime_UTR_variant	Exon 10 of 12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 2 with or without anosmia Uncertain:1

May 04, 2023

Reproductive Endocrine Unit, Massachusetts General Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The variant has been classified as VUS based on the variant meeting the following ACMG Criteria: PM2,PP2. -

Hypogonadotropic hypogonadism 2 with anosmia Other:1

May 02, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;.;D;.;.;.;.;.;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;.;T;T;.;T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	-0.060	.;.;N;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.7	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;T;D
Sift4G	Benign	0.64	T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	.;.;D;D;.;.;D;D;.;.
Vest4		0.77
MutPred		0.46		.;.;Loss of ubiquitination at K482 (P = 0.0768);.;.;.;.;.;.;.;
MVP		0.85
MPC		0.76
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs397515444; hg19: chr8-38275493;