rs3135898

Variant names:

• chr4-1806195-G-A
• rs3135898
• NM_000142.5:c.1959+22G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1806195-G-A
• chr4-1806195-G-C
• chr4-1806195-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000142.5(FGFR3):​c.1959+22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,611,346 control chromosomes in the GnomAD database, including 571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (59 hom., cov: 34)
  • Exomes 𝑓: 0.020 (512 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.23
• Publications: 10 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-1806195-G-A is Benign according to our data. Variant chr4-1806195-G-A is described in ClinVar as Benign. ClinVar VariationId is 255335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0619 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	NM_000142.5	MANE Select	c.1959+22G>A		intron	N/A	NP_000133.1
	FGFR3	NM_001163213.2		c.1965+22G>A		intron	N/A	NP_001156685.1
	FGFR3	NM_001354809.2		c.1962+22G>A		intron	N/A	NP_001341738.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.1959+22G>A		intron	N/A	ENSP00000414914.2
	FGFR3	ENST00000481110.7	TSL:1	c.1962+22G>A		intron	N/A	ENSP00000420533.2
	FGFR3	ENST00000352904.6	TSL:1	c.1623+22G>A		intron	N/A	ENSP00000231803.1

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2861 AN: 152208 Hom.: 58 Cov.: 34

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0472

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0307 AC: 7603 AN: 248012 AF XY: 0.0301

Gnomad AFR exome AF: 0.00347

Gnomad AMR exome AF: 0.0949

Gnomad ASJ exome AF: 0.0421

Gnomad EAS exome AF: 0.000273

Gnomad FIN exome AF: 0.00945

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0198 AC: 28862 AN: 1459020 Hom.: 512 Cov.: 38 AF XY: 0.0206 AC XY: 14959 AN XY: 725816

African (AFR) AF: 0.00281 AC: 94 AN: 33450

American (AMR) AF: 0.0909 AC: 4048 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 1105 AN: 26108

East Asian (EAS) AF: 0.000555 AC: 22 AN: 39658

South Asian (SAS) AF: 0.0509 AC: 4390 AN: 86210

European-Finnish (FIN) AF: 0.0110 AC: 578 AN: 52310

Middle Eastern (MID) AF: 0.0317 AC: 183 AN: 5764

European-Non Finnish (NFE) AF: 0.0155 AC: 17198 AN: 1110672

Other (OTH) AF: 0.0206 AC: 1244 AN: 60302

GnomAD4 genome AF: 0.0188 AC: 2866 AN: 152326 Hom.: 59 Cov.: 34 AF XY: 0.0202 AC XY: 1503 AN XY: 74476

African (AFR) AF: 0.00438 AC: 182 AN: 41576

American (AMR) AF: 0.0653 AC: 999 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0470 AC: 227 AN: 4826

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1101 AN: 68022

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.0212 Hom.: 11

Bravo AF: 0.0231

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.0
DANN	Benign	0.91
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs3135898; hg19: chr4-1807922; COSMIC: COSV53415329;