rs7688609

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000142.5(FGFR3):c.1953G>A(p.Thr651Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,613,064 control chromosomes in the GnomAD database, including 795,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 70557 hom., cov: 37)

Exomes 𝑓: 1.0 ( 724779 hom. )

Consequence

FGFR3
NM_000142.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.107

Publications

62 publications found

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 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 4-1806167-G-A is Benign according to our data. Variant chr4-1806167-G-A is described in ClinVar as Benign. ClinVar VariationId is 873164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.107 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5 link	c.1953G>A	p.Thr651Thr	synonymous_variant	Exon 14 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.1953G>A	p.Thr651Thr	synonymous_variant	Exon 14 of 18	5	NM_000142.5	ENSP00000414914.2		P22607-1

Frequencies

GnomAD3 genomes

AF:

0.961

AC:

146205

AN:

152198

Hom.:

70535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.862

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.988

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.977

GnomAD2 exomes

AF:

0.990

AC:

246589

AN:

249150

AF XY:

0.993

show subpopulations

Gnomad AFR exome

AF:

0.858

Gnomad AMR exome

AF:

0.994

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.995

GnomAD4 exome

AF:

0.996

AC:

1454795

AN:

1460748

Hom.:

724779

Cov.:

AF XY:

0.997

AC XY:

724154

AN XY:

726680

show subpopulations

African (AFR)

AF:

0.857

AC:

28689

AN:

33468

American (AMR)

AF:

0.993

AC:

44366

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26118

AN:

26118

East Asian (EAS)

AF:

1.00

AC:

39686

AN:

39686

South Asian (SAS)

AF:

1.00

AC:

86195

AN:

86234

European-Finnish (FIN)

AF:

1.00

AC:

52676

AN:

52676

Middle Eastern (MID)

AF:

0.996

AC:

5743

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111562

AN:

1111764

Other (OTH)

AF:

0.990

AC:

59760

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

357

714

1070

1427

1784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21666

43332

64998

86664

108330

<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:

0.960

AC:

146280

AN:

152316

Hom.:

70557

Cov.:

AF XY:

0.962

AC XY:

71641

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.861

AC:

35774

AN:

41550

American (AMR)

AF:

0.988

AC:

15134

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5174

AN:

5174

South Asian (SAS)

AF:

0.999

AC:

4828

AN:

4832

European-Finnish (FIN)

AF:

1.00

AC:

10630

AN:

10630

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

67998

AN:

68026

Other (OTH)

AF:

0.977

AC:

2066

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

276

553

829

1106

1382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.983

Hom.:

117983

Bravo

AF:

0.954

Asia WGS

AF:

0.988

AC:

3438

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

0.999

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Squamous cell lung carcinoma

Benign:1

May 05, 2020

Faculté Pluridciplinaire Nador, Université Mohamed Premier

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing;in vivo

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

4.6

(source)

DANN

Benign

0.80

PhyloP100

0.11

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over