8-38413783-G-C

Variant names:

• chr8-38413783-G-C
• rs56234888
• NM_023110.3:c.2314C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_023110.3(FGFR1):​c.2314C>G​(p.Pro772Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P772S) 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: 4.90

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2911824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR1	NM_023110.3	c.2314C>G	p.Pro772Ala	missense_variant	Exon 18 of 18	ENST00000447712.7	NP_075598.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR1	ENST00000447712.7	c.2314C>G	p.Pro772Ala	missense_variant	Exon 18 of 18	1	NM_023110.3	ENSP00000400162.2
FGFR1	ENST00000397091.9	c.2308C>G	p.Pro770Ala	missense_variant	Exon 18 of 18	1		ENSP00000380280.5
FGFR1	ENST00000397108.8	c.2308C>G	p.Pro770Ala	missense_variant	Exon 19 of 19	1		ENSP00000380297.4
FGFR1	ENST00000397113.6	c.2308C>G	p.Pro770Ala	missense_variant	Exon 18 of 18	2		ENSP00000380302.2
FGFR1	ENST00000356207.9	c.2047C>G	p.Pro683Ala	missense_variant	Exon 17 of 17	1		ENSP00000348537.5
FGFR1	ENST00000397103.5	c.2047C>G	p.Pro683Ala	missense_variant	Exon 16 of 16	5		ENSP00000380292.1
FGFR1	ENST00000326324.10	c.2041C>G	p.Pro681Ala	missense_variant	Exon 17 of 17	1		ENSP00000327229.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;.;D;.;.;.;.;.;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;.;D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	.;.;M;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.019	D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T
Polyphen		0.96, 0.98, 0.88	.;.;D;D;.;.;P;P;.;.
Vest4		0.16
MutPred		0.28		.;.;Loss of disorder (P = 0.07);.;.;.;.;.;.;.;
MVP		0.74
MPC		1.7
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.53
gMVP		0.44

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: rs56234888; hg19: chr8-38271301;