4-1799344-G-C

Variant names:

• chr4-1799344-G-C
• rs369232922
• NM_000142.5:c.200G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000142.5(FGFR3):​c.200G>C​(p.Gly67Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G67G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.323

Genes affected

FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist 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 acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044391215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.200G>C	p.Gly67Ala	missense_variant	Exon 3 of 18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.200G>C	p.Gly67Ala	missense_variant	Exon 3 of 18	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460238 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726406

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thanatophoric dysplasia, type 2 Uncertain:1

Aug 01, 2020

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 3 of the FGFR3 gene that results in the amino acid substitution of Alanine for Glycine at codon 67 was detected. The observed variant c.200G>C (p.Gly67Ala) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT and MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.0
DANN	Benign	0.90
DEOGEN2	Benign	0.36	T;T;.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.80	T;T;T;T;T;.
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.044	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.44	N;.;N;N;.;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.41	N;N;N;N;.;N
REVEL	Benign	0.015
Sift	Benign	1.0	T;T;T;T;.;T
Sift4G	Benign	0.85	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;.;B
Vest4		0.18
MutPred		0.31		Loss of disorder (P = 0.1052);Loss of disorder (P = 0.1052);Loss of disorder (P = 0.1052);Loss of disorder (P = 0.1052);Loss of disorder (P = 0.1052);Loss of disorder (P = 0.1052);
MVP		0.42
MPC		0.31
ClinPred		0.080	T
GERP RS		-0.0076
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.24

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: rs369232922; hg19: chr4-1801071; COSMIC: COSV105835183; COSMIC: COSV105835183;