dbSNP rs2234909: FGFR3:p.Asn294Asn (chr4-1801977-T-C) – ACMG Classification: Benign (-21 pts)

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.882T>C(p.Asn294Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,612,450 control chromosomes in the GnomAD database, including 21,902 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3852 hom., cov: 33)

Exomes 𝑓: 0.15 ( 18050 hom. )

Consequence

FGFR3
NM_000142.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.695

Publications

43 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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P, Ambry Genetics, ClinGen
Crouzon syndrome-acanthosis nigricans syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, Genomics England PanelApp, G2P
hypochondroplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P, Ambry Genetics
lacrimoauriculodentodigital syndrome 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Muenke syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen, Genomics England PanelApp
thanatophoric dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
thanatophoric dysplasia type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Ambry Genetics, Genomics England PanelApp
thanatophoric dysplasia type 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
camptodactyly-tall stature-scoliosis-hearing loss syndrome
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
severe achondroplasia-developmental delay-acanthosis nigricans syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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=-0.79).

BP6

Variant 4-1801977-T-C is Benign according to our data. Variant chr4-1801977-T-C is described in ClinVar as Benign. ClinVar VariationId is 255346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.695 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000142.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGFR3	NM_000142.5	MANE Select	c.882T>C	p.Asn294Asn	synonymous	Exon 7 of 18	NP_000133.1	P22607-1
FGFR3	NM_001163213.2		c.882T>C	p.Asn294Asn	synonymous	Exon 7 of 18	NP_001156685.1	P22607-2
FGFR3	NM_001354809.2		c.882T>C	p.Asn294Asn	synonymous	Exon 7 of 18	NP_001341738.1	X5D2G8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.882T>C	p.Asn294Asn	synonymous	Exon 7 of 18	ENSP00000414914.2	P22607-1
FGFR3	ENST00000481110.7	TSL:1	c.882T>C	p.Asn294Asn	synonymous	Exon 7 of 17	ENSP00000420533.2	F8W9L4
FGFR3	ENST00000352904.6	TSL:1	c.882T>C	p.Asn294Asn	synonymous	Exon 6 of 15	ENSP00000231803.1	P22607-3

Frequencies

GnomAD3 genomes

AF:

0.200

AC:

30446

AN:

151954

Hom.:

3823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.353

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.144

Gnomad ASJ

AF:

0.212

Gnomad EAS

AF:

0.0695

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.205

GnomAD2 exomes

AF:

0.160

AC:

39814

AN:

248846

AF XY:

0.160

show subpopulations

Gnomad AFR exome

AF:

0.355

Gnomad AMR exome

AF:

0.124

Gnomad ASJ exome

AF:

0.218

Gnomad EAS exome

AF:

0.0457

Gnomad FIN exome

AF:

0.134

Gnomad NFE exome

AF:

0.148

Gnomad OTH exome

AF:

0.167

GnomAD4 exome

AF:

0.151

AC:

220041

AN:

1460376

Hom.:

18050

Cov.:

AF XY:

0.152

AC XY:

110627

AN XY:

726476

show subpopulations

African (AFR)

AF:

0.362

AC:

12110

AN:

33470

American (AMR)

AF:

0.127

AC:

5659

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

5831

AN:

26122

East Asian (EAS)

AF:

0.0927

AC:

3680

AN:

39690

South Asian (SAS)

AF:

0.209

AC:

18066

AN:

86254

European-Finnish (FIN)

AF:

0.135

AC:

7057

AN:

52224

Middle Eastern (MID)

AF:

0.249

AC:

1438

AN:

5766

European-Non Finnish (NFE)

AF:

0.140

AC:

156110

AN:

1111796

Other (OTH)

AF:

0.167

AC:

10090

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

11896

23791

35687

47582

59478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5670

11340

17010

22680

28350

<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:

0.201

AC:

30525

AN:

152074

Hom.:

3852

Cov.:

AF XY:

0.198

AC XY:

14696

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.354

AC:

14667

AN:

41468

American (AMR)

AF:

0.144

AC:

2195

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

736

AN:

3466

East Asian (EAS)

AF:

0.0697

AC:

358

AN:

5138

South Asian (SAS)

AF:

0.201

AC:

967

AN:

4818

European-Finnish (FIN)

AF:

0.130

AC:

1382

AN:

10612

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.141

AC:

9616

AN:

67962

Other (OTH)

AF:

0.205

AC:

433

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1246

2491

3737

4982

6228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.169

Hom.:

1484

Bravo

AF:

0.209

Asia WGS

AF:

0.180

AC:

622

AN:

3478

EpiCase

AF:

0.155

EpiControl

AF:

0.154

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.6

(source)

DANN

Benign

0.55

PhyloP100

-0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over