chr4-1799760-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000142.5(FGFR3):c.393G>A(p.Ser131Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,613,040 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 16 hom. )

Consequence

FGFR3
NM_000142.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.96

Publications

4 publications found

Variant links:

COSMIC-nc: COSV99601019

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 -16 ACMG points.

BP6

Variant 4-1799760-G-A is Benign according to our data. Variant chr4-1799760-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00282 (430/152338) while in subpopulation NFE AF = 0.00429 (292/68020). AF 95% confidence interval is 0.00389. There are 0 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 AD,AR,SD gene

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.393G>A	p.Ser131Ser	synonymous	Exon 4 of 18	NP_000133.1	P22607-1
FGFR3	NM_001163213.2		c.393G>A	p.Ser131Ser	synonymous	Exon 4 of 18	NP_001156685.1	P22607-2
FGFR3	NM_001354809.2		c.393G>A	p.Ser131Ser	synonymous	Exon 4 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.393G>A	p.Ser131Ser	synonymous	Exon 4 of 18	ENSP00000414914.2	P22607-1
FGFR3	ENST00000481110.7	TSL:1	c.393G>A	p.Ser131Ser	synonymous	Exon 4 of 17	ENSP00000420533.2	F8W9L4
FGFR3	ENST00000352904.6	TSL:1	c.393G>A	p.Ser131Ser	synonymous	Exon 3 of 15	ENSP00000231803.1	P22607-3

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

428

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00428

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00280

AC:

699

AN:

249766

AF XY:

0.00272

show subpopulations

Gnomad AFR exome

AF:

0.000809

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.00300

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00292

Gnomad NFE exome

AF:

0.00407

Gnomad OTH exome

AF:

0.00345

GnomAD4 exome

AF:

0.00364

AC:

5323

AN:

1460702

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

2588

AN XY:

726652

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

33480

American (AMR)

AF:

0.00224

AC:

100

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00150

AC:

129

AN:

86242

European-Finnish (FIN)

AF:

0.00304

AC:

159

AN:

52368

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00413

AC:

4587

AN:

1111928

Other (OTH)

AF:

0.00277

AC:

167

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

317

633

950

1266

1583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<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:

0.00282

AC:

430

AN:

152338

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

41586

American (AMR)

AF:

0.00281

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00429

AC:

292

AN:

68020

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

120

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:

0.00360

Hom.:

Bravo

AF:

0.00275

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00453

EpiControl

AF:

0.00368

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

not specified (4)

Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.6

(source)

DANN

Benign

0.78

PhyloP100

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.36

Position offset: 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