4-1801844-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_001163213.2(FGFR3):c.749C>G(p.Pro250Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,606,994 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P250L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

FGFR3
NM_001163213.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:45O:2

Conservation

PhyloP100: 5.85

Publications

178 publications found

Variant links:

COSMIC-nc: COSV108076996

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 Gene-Disease associations (from GenCC):

achondroplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Crouzon syndrome-acanthosis nigricans syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
hypochondroplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
lacrimoauriculodentodigital syndrome 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Muenke syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
thanatophoric dysplasia type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, ClinGen
thanatophoric dysplasia type 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
camptodactyly-tall stature-scoliosis-hearing loss syndrome
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
severe achondroplasia-developmental delay-acanthosis nigricans syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
isolated brachycephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated plagiocephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
LADD syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
LADD syndrome 1
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

FGFR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001163213.2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 4-1801844-C-G is Pathogenic according to our data. Variant chr4-1801844-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163213.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FGFR3	NM_000142.5	MANE Select	c.749C>G	p.Pro250Arg	missense	Exon 7 of 18	NP_000133.1
FGFR3	NM_001163213.2		c.749C>G	p.Pro250Arg	missense	Exon 7 of 18	NP_001156685.1
FGFR3	NM_001354809.2		c.749C>G	p.Pro250Arg	missense	Exon 7 of 18	NP_001341738.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.749C>G	p.Pro250Arg	missense	Exon 7 of 18	ENSP00000414914.2
FGFR3	ENST00000481110.7	TSL:1	c.749C>G	p.Pro250Arg	missense	Exon 7 of 17	ENSP00000420533.2
FGFR3	ENST00000352904.6	TSL:1	c.749C>G	p.Pro250Arg	missense	Exon 6 of 15	ENSP00000231803.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000418

AC:

AN:

238970

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1454808

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722916

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33342

American (AMR)

AF:

0.0000225

AC:

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25884

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.00

AC:

AN:

85942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51610

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1108222

Other (OTH)

AF:

0.0000333

AC:

AN:

60002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Muenke syndrome (21)

not provided (10)

Achondroplasia (3)

FGFR3-related disorder (3)

Abnormality of the nervous system (1)

Achondroplasia;C0005684:Malignant tumor of urinary bladder;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;C5774286:Lacrimoauriculodentodigital syndrome 2 (1)

Craniosynostosis syndrome (1)

Crouzon syndrome;C0036572:Seizure;C0266294:Unilateral renal agenesis;C1306710:Facial asymmetry;C1856266:Coronal craniosynostosis;C3806604:Infantile axial hypotonia;C4316903:Generalized non-motor (absence) seizure (1)

FGFR3-related chondrodysplasia (1)

Hypochondroplasia (1)

Inborn genetic diseases (1)

Saethre-Chotzen syndrome (1)

Achondroplasia;C0410529:Hypochondroplasia;C1864436:Muenke syndrome;C1868678:Thanatophoric dysplasia type 1;C2677099:Crouzon syndrome-acanthosis nigricans syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.5

PhyloP100

5.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

Sift4G

Benign

0.23

Polyphen

1.0

Vest4

0.73

MutPred

0.89

Loss of glycosylation at P250 (P = 0.0271)

MVP

0.96

MPC

0.35

ClinPred

0.75

GERP RS

3.1

PromoterAI

0.026

Neutral

(source)

Varity_R

0.95

gMVP

0.90

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over