dbSNP rs3135885: FGFR3:c.1075+5C>T (chr4-1803841-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_001354809.2(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_001354809.2 splice_region, intron

Scores

Splicing: ADA: 0.00005694

Clinical Significance

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

Conservation

PhyloP100: -0.581

Publications

9 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 -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 VariationId is 255323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FGFR3	NM_000142.5	MANE Select	c.1075+5C>T	splice_region intron	N/A	NP_000133.1
FGFR3	NM_001163213.2		c.1082-489C>T	intron	N/A	NP_001156685.1
FGFR3	NM_001354809.2		c.1075+5C>T	splice_region intron	N/A	NP_001341738.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.1075+5C>T	splice_region intron	N/A	ENSP00000414914.2
FGFR3	ENST00000481110.7	TSL:1	c.1075+5C>T	splice_region intron	N/A	ENSP00000420533.2
FGFR3	ENST00000352904.6	TSL:1	c.931-983C>T	intron	N/A	ENSP00000231803.1

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

African (AFR)

AF:

0.0386

AC:

1291

AN:

33468

American (AMR)

AF:

0.00917

AC:

410

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0290

AC:

759

AN:

26132

East Asian (EAS)

AF:

0.0219

AC:

871

AN:

39696

South Asian (SAS)

AF:

0.0169

AC:

1458

AN:

86236

European-Finnish (FIN)

AF:

0.000605

AC:

AN:

52888

Middle Eastern (MID)

AF:

0.0399

AC:

229

AN:

5736

European-Non Finnish (NFE)

AF:

0.00448

AC:

4976

AN:

1111562

Other (OTH)

AF:

0.0117

AC:

705

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

603

1206

1810

2413

3016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.0380

AC:

1578

AN:

41572

American (AMR)

AF:

0.0133

AC:

203

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0262

AC:

AN:

3472

East Asian (EAS)

AF:

0.0162

AC:

AN:

5188

South Asian (SAS)

AF:

0.0155

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00570

AC:

388

AN:

68038

Other (OTH)

AF:

0.0175

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

130

261

391

522

652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (5)

Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.4

(source)

DANN

Benign

0.91

PhyloP100

-0.58

RBP_binding_hub_radar

0.77

RBP_regulation_power_radar

1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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