rs56240927

chr4-1804906-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000142.5(FGFR3):c.1349C>T(p.Thr450Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 1,549,932 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T450T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00070 (8 hom.)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.65

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050892234).
• BP6: Variant 4-1804906-C-T is Benign according to our data. Variant chr4-1804906-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1804906-C-T is described in Lovd as [Benign]. Variant chr4-1804906-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000972 (148/152210) while in subpopulation EAS AF= 0.0155 (80/5148). AF 95% confidence interval is 0.0128. There are 1 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.1349C>T	p.Thr450Met	missense_variant	10/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.1349C>T	p.Thr450Met	missense_variant	10/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152092 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0155

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00129 AC: 201 AN: 156020 Hom.: 1 AF XY: 0.00122 AC XY: 100 AN XY: 82182

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.000485

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0145

Gnomad SAS exome AF: 0.000219

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000454

GnomAD4 exome AF: 0.000703 AC: 982 AN: 1397722 Hom.: 8 Cov.: 33 AF XY: 0.000682 AC XY: 470 AN XY: 689420

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.000318

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.000341

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000742

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152210 Hom.: 1 Cov.: 34 AF XY: 0.000954 AC XY: 71 AN XY: 74414

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0155

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000912 Hom.: 0

Bravo AF: 0.00130

ESP6500AA AF: 0.00195 AC: 8

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000806 AC: 67

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	FGFR3: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 01, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 08, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	18
Dann	Benign	0.077
DEOGEN2	Benign	0.37	T;T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.89	D;D;D;D;.
MetaRNN	Benign	0.0051	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-1.6	N;.;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.6	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.44	T;T;T;T;T
Polyphen		0.0070	B;B;B;B;B
Vest4		0.090
MVP		0.66
MPC		0.29
ClinPred		0.00026	T
GERP RS		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.019
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs56240927; hg19: chr4-1806633; COSMIC: COSV53417024; COSMIC: COSV53417024;