4-1804404-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000142.5(FGFR3):c.1150T>C(p.Phe384Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,613,186 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F384I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0045 ( 30 hom. )

Consequence

FGFR3
NM_000142.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.767

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000142.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0062094927).

BP6

Variant 4-1804404-T-C is Benign according to our data. Variant chr4-1804404-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 134404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1804404-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00334 (509/152294) while in subpopulation NFE AF= 0.00615 (418/68010). AF 95% confidence interval is 0.00566. There are 1 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5 linkuse as main transcript	c.1150T>C	p.Phe384Leu	missense_variant	9/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8 linkuse as main transcript	c.1150T>C	p.Phe384Leu	missense_variant	9/18	5	NM_000142.5	P4	P22607-1

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

509

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00615

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00329

AC:

823

AN:

250474

Hom.:

AF XY:

0.00334

AC XY:

452

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.000700

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000791

Gnomad NFE exome

AF:

0.00590

Gnomad OTH exome

AF:

0.00393

GnomAD4 exome

AF:

0.00453

AC:

6620

AN:

1460892

Hom.:

Cov.:

AF XY:

0.00448

AC XY:

3258

AN XY:

726768

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00302

Gnomad4 ASJ exome

AF:

0.000920

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.000888

Gnomad4 NFE exome

AF:

0.00551

Gnomad4 OTH exome

AF:

0.00381

GnomAD4 genome

AF:

0.00334

AC:

509

AN:

152294

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

221

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00615

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00410

Hom.:

Bravo

AF:

0.00377

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00303

AC:

368

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00867

EpiControl

AF:

0.00759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Nov 02, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	FGFR3: BP4, BS2 -

not specified

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2016	- -

Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0346629:Colorectal cancer;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1336708:Germ cell tumor of testis;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 18, 2022

- -

Hypochondroplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Uncertain

0.59

D;T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.0062

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.44

N;.;.

MutationTaster

Benign

1.0

D;D;N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.48

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.092

MutPred

0.16

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;

MVP

0.81

MPC

0.33

ClinPred

0.010

GERP RS

3.6

Varity_R

0.20

gMVP

0.50

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