Variant rs373496046 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000142.5(FGFR3):c.1000G>A(p.Ala334Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

FGFR3
NM_000142.5 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 9.75

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR3	NM_000142.5 linkuse as main transcript	c.1000G>A	p.Ala334Thr	missense_variant	8/18	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8 linkuse as main transcript	c.1000G>A	p.Ala334Thr	missense_variant	8/18	5	NM_000142.5	ENSP00000414914	P4	P22607-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250872

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Variant of unknown significance

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Dec 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

D;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.054

T;D

Polyphen

0.99

D;D

Vest4

0.89

MVP

0.86

ClinPred

0.75

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over