rs3135885

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000142.5(FGFR3):c.1075+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00819 in 1,613,132 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 34 hom., cov: 34)

Exomes 𝑓: 0.0073 ( 129 hom. )

Consequence

FGFR3
NM_000142.5 splice_region, intron

Scores

Splicing: ADA: 0.00005694

Clinical Significance

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

Conservation

PhyloP100: -0.581

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 4-1803841-C-T is Benign according to our data. Variant chr4-1803841-C-T is described in ClinVar as [Benign]. Clinvar id is 255323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1803841-C-T is described in Lovd as [Benign]. Variant chr4-1803841-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0163 (2488/152340) while in subpopulation AFR AF = 0.038 (1578/41572). AF 95% confidence interval is 0.0364. There are 34 homozygotes in GnomAd4. There are 1196 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 34 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5 link	c.1075+5C>T		splice_region_variant, intron_variant	Intron 8 of 17	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.1075+5C>T		splice_region_variant, intron_variant	Intron 8 of 17	5	NM_000142.5	ENSP00000414914.2		P22607-1

Frequencies

GnomAD3 genomes

AF:

0.0163

AC:

2484

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0379

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0262

Gnomad EAS

AF:

0.0162

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00572

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0108

AC:

2713

AN:

250498

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.0366

Gnomad AMR exome

AF:

0.00856

Gnomad ASJ exome

AF:

0.0269

Gnomad EAS exome

AF:

0.0153

Gnomad FIN exome

AF:

0.000419

Gnomad NFE exome

AF:

0.00641

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.00735

AC:

10731

AN:

1460792

Hom.:

129

Cov.:

AF XY:

0.00773

AC XY:

5615

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.0386

AC:

1291

AN:

33468

Gnomad4 AMR exome

AF:

0.00917

AC:

410

AN:

44720

Gnomad4 ASJ exome

AF:

0.0290

AC:

759

AN:

26132

Gnomad4 EAS exome

AF:

0.0219

AC:

871

AN:

39696

Gnomad4 SAS exome

AF:

0.0169

AC:

1458

AN:

86236

Gnomad4 FIN exome

AF:

0.000605

AC:

AN:

52888

Gnomad4 NFE exome

AF:

0.00448

AC:

4976

AN:

1111562

Gnomad4 Remaining exome

AF:

0.0117

AC:

705

AN:

60354

Heterozygous variant carriers

603

1206

1810

2413

3016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<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:

0.0163

AC:

2488

AN:

152340

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

1196

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0380

AC:

0.0379582

AN:

0.0379582

Gnomad4 AMR

AF:

0.0133

AC:

0.013261

AN:

0.013261

Gnomad4 ASJ

AF:

0.0262

AC:

0.0262097

AN:

0.0262097

Gnomad4 EAS

AF:

0.0162

AC:

0.0161912

AN:

0.0161912

Gnomad4 SAS

AF:

0.0155

AC:

0.0155408

AN:

0.0155408

Gnomad4 FIN

AF:

0.000282

AC:

0.000282486

AN:

0.000282486

Gnomad4 NFE

AF:

0.00570

AC:

0.0057027

AN:

0.0057027

Gnomad4 OTH

AF:

0.0175

AC:

0.0175189

AN:

0.0175189

Heterozygous variant carriers

130

261

391

522

652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00879

Hom.:

Bravo

AF:

0.0176

Asia WGS

AF:

0.0290

AC:

100

AN:

3476

EpiCase

AF:

0.00802

EpiControl

AF:

0.00925

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 20, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Dec 06, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.4

DANN

Benign

0.91

RBP_binding_hub_radar

0.77

RBP_regulation_power_radar

1.9

Mutation Taster

=100/0

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000057

dbscSNV1_RF

Benign

0.0020

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