rs140594137

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_000142.5(FGFR3):c.1497C>T(p.Ala499Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 1,611,810 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00089 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -2.86

Variant links:

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]

FGFR3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 4-1805439-C-T is Benign according to our data. Variant chr4-1805439-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287881.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr4-1805439-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.86 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00101 (154/152338) while in subpopulation AMR AF= 0.00359 (55/15306). AF 95% confidence interval is 0.00283. There are 2 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5 link	c.1497C>T	p.Ala499Ala	synonymous_variant	Exon 11 of 18	ENST00000440486.8	NP_000133.1	P22607-1Q0IJ44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8 link	c.1497C>T	p.Ala499Ala	synonymous_variant	Exon 11 of 18	5	NM_000142.5	ENSP00000414914.2		P22607-1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000955

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000586

AC:

145

AN:

247454

Hom.:

AF XY:

0.000535

AC XY:

AN XY:

134646

show subpopulations

Gnomad AFR exome

AF:

0.000191

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000890

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000889

AC:

1297

AN:

1459472

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

634

AN XY:

725888

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.00107

Gnomad4 OTH exome

AF:

0.000796

GnomAD4 genome

AF:

0.00101

AC:

154

AN:

152338

Hom.:

Cov.:

AF XY:

0.000926

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000955

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000920

Hom.:

Bravo

AF:

0.00128

EpiCase

AF:

0.00120

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided