chr8-38419696-T-C

Position:

• chr8-38419696-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_023110.3(FGFR1):​c.1121A>G​(p.Tyr374Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR1 NM_023110.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.79

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 8-38419696-T-C is Pathogenic according to our data. Variant chr8-38419696-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 16287.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-38419696-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.1121A>G	p.Tyr374Cys	missense_variant	9/18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.1121A>G	p.Tyr374Cys	missense_variant	9/18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.1115A>G	p.Tyr372Cys	missense_variant	9/18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.1115A>G	p.Tyr372Cys	missense_variant	10/19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.1115A>G	p.Tyr372Cys	missense_variant	9/18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.854A>G	p.Tyr285Cys	missense_variant	8/17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.854A>G	p.Tyr285Cys	missense_variant	7/16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.848A>G	p.Tyr283Cys	missense_variant	8/17	1		ENSP00000327229.6
FGFR1	ENST00000487647.5	n.*812A>G		non_coding_transcript_exon_variant	8/12	1		ENSP00000435254.1
FGFR1	ENST00000487647.5	n.*812A>G		3_prime_UTR_variant	8/12	1		ENSP00000435254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Osteoglophonic dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;.;.;.;.;.;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;.;D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.1	.;.;M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.037	D;D;D;D;D;D;D;D;T;D
Polyphen		1.0	D;D;D;D;D;D;D;D;.;D
Vest4		0.83
MutPred		0.46		.;.;Loss of catalytic residue at Y374 (P = 0.1556);Loss of catalytic residue at Y374 (P = 0.1556);.;.;.;.;.;.;
MVP		0.94
MPC		0.81
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.58
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs121909631; hg19: chr8-38277214;