rs3135890

Variant names:

• chr4-1804792-C-T
• rs3135890
• NM_000142.5:c.1267-32C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-1804792-C-T
• chr4-1804792-C-A

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.1267-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,548,494 control chromosomes in the GnomAD database, including 10,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (957 hom., cov: 34)
  • Exomes 𝑓: 0.12 (9841 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.49
• Publications: 11 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: 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 4-1804792-C-T is Benign according to our data. Variant chr4-1804792-C-T is described in ClinVar as Benign. ClinVar VariationId is 255328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	NM_000142.5	MANE Select	c.1267-32C>T		intron	N/A	NP_000133.1	P22607-1
	FGFR3	NM_001163213.2		c.1273-32C>T		intron	N/A	NP_001156685.1	P22607-2
	FGFR3	NM_001354809.2		c.1267-29C>T		intron	N/A	NP_001341738.1	X5D2G8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.1267-32C>T		intron	N/A	ENSP00000414914.2	P22607-1
	FGFR3	ENST00000481110.7	TSL:1	c.1267-29C>T		intron	N/A	ENSP00000420533.2	F8W9L4
	FGFR3	ENST00000352904.6	TSL:1	c.931-32C>T		intron	N/A	ENSP00000231803.1	P22607-3

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16176 AN: 152198 Hom.: 958 Cov.: 34

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.0604

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.121 AC: 18775 AN: 154938 AF XY: 0.116

Gnomad AFR exome AF: 0.0568

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.206

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.115 AC: 160569 AN: 1396178 Hom.: 9841 Cov.: 34 AF XY: 0.113 AC XY: 78126 AN XY: 688682

African (AFR) AF: 0.0554 AC: 1749 AN: 31546

American (AMR) AF: 0.189 AC: 6751 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2809 AN: 25174

East Asian (EAS) AF: 0.200 AC: 7135 AN: 35730

South Asian (SAS) AF: 0.0538 AC: 4258 AN: 79162

European-Finnish (FIN) AF: 0.0997 AC: 4770 AN: 47836

Middle Eastern (MID) AF: 0.133 AC: 596 AN: 4484

European-Non Finnish (NFE) AF: 0.116 AC: 125659 AN: 1078702

Other (OTH) AF: 0.118 AC: 6842 AN: 57844

GnomAD4 genome AF: 0.106 AC: 16178 AN: 152316 Hom.: 957 Cov.: 34 AF XY: 0.107 AC XY: 7986 AN XY: 74470

African (AFR) AF: 0.0585 AC: 2431 AN: 41572

American (AMR) AF: 0.167 AC: 2562 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 366 AN: 3472

East Asian (EAS) AF: 0.202 AC: 1043 AN: 5172

South Asian (SAS) AF: 0.0608 AC: 294 AN: 4834

European-Finnish (FIN) AF: 0.110 AC: 1171 AN: 10612

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7873 AN: 68024

Other (OTH) AF: 0.109 AC: 230 AN: 2116

Alfa AF: 0.0950 Hom.: 332

Bravo AF: 0.111

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.0030
DANN	Benign	0.86
PhyloP100		-6.5
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)		0.010		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: rs3135890; hg19: chr4-1806519; COSMIC: COSV53392324; COSMIC: COSV53392324;