4-1805561-G-T

Position:

• chr4-1805561-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000142.5(FGFR3):​c.1537G>T​(p.Asp513Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. D513N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGFR3 NM_000142.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.49

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Protein kinase (size 289) in uniprot entity FGFR3_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_000142.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-1805561-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.1537G>T	p.Asp513Tyr	missense_variant, splice_region_variant	12/18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.1537G>T	p.Asp513Tyr	missense_variant, splice_region_variant	12/18	5	NM_000142.5	ENSP00000414914	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460796 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726704

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.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 513 of the FGFR3 protein (p.Asp513Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FGFR3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Levy-Hollister syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 25, 2020

A heterozygous missense variant was identified, NM_000142.4(FGFR3):c.1537G>T in exon 12 of 18 of the FGFR3 gene. This substitution is predicted to create a major amino acid change from an aspartic acid to a tyrosine at position 513 of the protein; NP_000133.1(FGFR3):p.(Asp513Tyr). The aspartic acid at this position has low conservation (100 vertebrates, UCSC), and is located within the protein kinase domain (NCBI, PDB). In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database however, three alternative residue changes have been reported in the gnomAD database at the highest frequency of 0.005%. This variant has not previously been reported in clinical cases. A different variant in the same codon resulting in a change to an asparagine has been shown to cause LADD syndrome (Rohmann E. et al. (2006), ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Benign	0.89
DEOGEN2	Pathogenic	0.90	D;D;.;.;.
Eigen	Benign	0.041
Eigen_PC	Benign	-0.056
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;.
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.7	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.8	D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.66
MutPred		0.59		Loss of disorder (P = 0.0055);.;.;.;.;
MVP		0.91
MPC		1.1
ClinPred		0.95	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121913112; hg19: chr4-1807288;