chr4-1799815-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000142.5(FGFR3):c.445+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,612,658 control chromosomes in the GnomAD database, including 3,839 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 1986 hom., cov: 33)

Exomes 𝑓: 0.015 ( 1853 hom. )

Consequence

FGFR3
NM_000142.5 splice_region, intron

Scores

Splicing: ADA: 0.009277

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.14

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 4-1799815-A-G is Benign according to our data. Variant chr4-1799815-A-G is described in ClinVar as [Benign]. Clinvar id is 255341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1799815-A-G is described in Lovd as [Benign]. Variant chr4-1799815-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5 link	c.445+3A>G		splice_region_variant, intron_variant	Intron 4 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.445+3A>G		splice_region_variant, intron_variant	Intron 4 of 17	5	NM_000142.5	ENSP00000414914.2		P22607-1

Frequencies

GnomAD3 genomes

AF:

0.0927

AC:

14096

AN:

152110

Hom.:

1967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.303

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0391

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.0254

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00676

Gnomad OTH

AF:

0.0731

GnomAD3 exomes

AF:

0.0310

AC:

7708

AN:

248904

Hom.:

798

AF XY:

0.0255

AC XY:

3451

AN XY:

135116

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.0204

Gnomad ASJ exome

AF:

0.0265

Gnomad EAS exome

AF:

0.0226

Gnomad SAS exome

AF:

0.0163

Gnomad FIN exome

AF:

0.000373

Gnomad NFE exome

AF:

0.00717

Gnomad OTH exome

AF:

0.0224

GnomAD4 exome

AF:

0.0154

AC:

22544

AN:

1460430

Hom.:

1853

Cov.:

AF XY:

0.0148

AC XY:

10731

AN XY:

726514

show subpopulations

Gnomad4 AFR exome

AF:

0.312

Gnomad4 AMR exome

AF:

0.0222

Gnomad4 ASJ exome

AF:

0.0285

Gnomad4 EAS exome

AF:

0.0266

Gnomad4 SAS exome

AF:

0.0181

Gnomad4 FIN exome

AF:

0.000612

Gnomad4 NFE exome

AF:

0.00495

Gnomad4 OTH exome

AF:

0.0317

GnomAD4 genome

AF:

0.0930

AC:

14164

AN:

152228

Hom.:

1986

Cov.:

AF XY:

0.0891

AC XY:

6636

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.304

Gnomad4 AMR

AF:

0.0391

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.0255

Gnomad4 SAS

AF:

0.0155

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00675

Gnomad4 OTH

AF:

0.0733

Alfa

AF:

0.0486

Hom.:

470

Bravo

AF:

0.105

Asia WGS

AF:

0.0600

AC:

207

AN:

3476

EpiCase

AF:

0.00894

EpiControl

AF:

0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 27, 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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic 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:4

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

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0093

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: -15

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