rs2305178

chr4-1799337-G-Achr4-1799337-G-C

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.193G>A(p.Gly65Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 1,612,544 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G65V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (14 hom.)
• Consequence: FGFR3 NM_000142.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.400

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=0.0055094957).
• BP6: Variant 4-1799337-G-A is Benign according to our data. Variant chr4-1799337-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1799337-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00115 (175/152346) while in subpopulation EAS AF= 0.0149 (77/5180). AF 95% confidence interval is 0.0122. There are 1 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.193G>A	p.Gly65Arg	missense_variant	3/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.193G>A	p.Gly65Arg	missense_variant	3/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00108 AC: 263 AN: 244396 Hom.: 1 AF XY: 0.000959 AC XY: 128 AN XY: 133442

Gnomad AFR exome AF: 0.00218

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0117

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000276

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000772 AC: 1127 AN: 1460198 Hom.: 14 Cov.: 32 AF XY: 0.000786 AC XY: 571 AN XY: 726374

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0231

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74504

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0149

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000202 Hom.: 0

Bravo AF: 0.00108

ESP6500AA AF: 0.00274 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 20, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2019	This variant is associated with the following publications: (PMID: 28471124, 29072634, 22903874) -

not specified Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 23, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.40	T;T;.;.;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.70	T;T;T;T;T;.
MetaRNN	Benign	0.0055	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.45	N;.;N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.22	N;N;N;N;.;N
REVEL	Benign	0.042
Sift	Benign	0.10	T;T;T;D;.;D
Sift4G	Benign	0.13	T;D;T;T;T;T
Polyphen		0.0	B;B;B;B;.;B
Vest4		0.24
MutPred		0.40		Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP		0.49
MPC		0.34
ClinPred		0.00095	T
GERP RS		0.70
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.048
gMVP		0.30

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: rs2305178; hg19: chr4-1801064; COSMIC: COSV53402176; COSMIC: COSV53402176;