NM_000142.5:c.109G>A

Variant names:

• chr4-1794043-G-A
• rs1553842213
• NM_000142.5:c.109G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000142.5(FGFR3):​c.109G>A​(p.Glu37Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,245,626 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E37D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FGFR3 NM_000142.5 missense, splice_region
• Scores: Splicing: ADA: 0.9938
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.04
• Publications: 0 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)

ENSG00000305534 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.109G>A	p.Glu37Lys	missense splice_region	Exon 2 of 18	NP_000133.1
	FGFR3	NM_001163213.2		c.109G>A	p.Glu37Lys	missense splice_region	Exon 2 of 18	NP_001156685.1
	FGFR3	NM_001354809.2		c.109G>A	p.Glu37Lys	missense splice_region	Exon 2 of 18	NP_001341738.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.109G>A	p.Glu37Lys	missense splice_region	Exon 2 of 18	ENSP00000414914.2
	FGFR3	ENST00000481110.7	TSL:1	c.109G>A	p.Glu37Lys	missense splice_region	Exon 2 of 17	ENSP00000420533.2
	FGFR3	ENST00000352904.6	TSL:1	c.109G>A	p.Glu37Lys	missense splice_region	Exon 1 of 15	ENSP00000231803.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000120 AC: 15 AN: 1245626 Hom.: 0 Cov.: 26 AF XY: 0.0000147 AC XY: 9 AN XY: 610588

African (AFR) AF: 0.00 AC: 0 AN: 25682

American (AMR) AF: 0.00 AC: 0 AN: 22014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20318

East Asian (EAS) AF: 0.00 AC: 0 AN: 28472

South Asian (SAS) AF: 0.00 AC: 0 AN: 56838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5066

European-Non Finnish (NFE) AF: 0.0000141 AC: 14 AN: 994742

Other (OTH) AF: 0.0000200 AC: 1 AN: 49926

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.27
Sift	Benign	0.34	T
Sift4G	Benign	0.86	T
Polyphen		0.18	B
Vest4		0.48
MutPred		0.41		Gain of ubiquitination at E37 (P = 0.0077)
MVP		0.92
MPC		0.36
ClinPred		0.11	T
GERP RS		1.0
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.054
gMVP		0.34
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.72
SpliceAI score (max)		0.12		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: rs1553842213; hg19: chr4-1795770;