4-1803751-C-T

Variant names:

• chr4-1803751-C-T
• rs2305185
• NM_000142.5:c.990C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000142.5(FGFR3):​c.990C>T​(p.Thr330Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000984 in 1,614,086 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T330T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (4 hom., cov: 34)
  • Exomes 𝑓: 0.00095 (23 hom.)
• Consequence: FGFR3 NM_000142.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.631
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 4-1803751-C-T is Benign according to our data. Variant chr4-1803751-C-T is described in ClinVar as Benign. ClinVar VariationId is 465358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.631 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00129 (197/152346) while in subpopulation EAS AF = 0.0369 (191/5170). AF 95% confidence interval is 0.0327. There are 4 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD,SD gene

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.990C>T	p.Thr330Thr	synonymous	Exon 8 of 18	NP_000133.1	P22607-1
	FGFR3	NM_001354809.2		c.990C>T	p.Thr330Thr	synonymous	Exon 8 of 18	NP_001341738.1	X5D2G8
	FGFR3	NM_001354810.2		c.990C>T	p.Thr330Thr	synonymous	Exon 8 of 17	NP_001341739.1	F8W9L4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.990C>T	p.Thr330Thr	synonymous	Exon 8 of 18	ENSP00000414914.2	P22607-1
	FGFR3	ENST00000481110.7	TSL:1	c.990C>T	p.Thr330Thr	synonymous	Exon 8 of 17	ENSP00000420533.2	F8W9L4
	FGFR3	ENST00000352904.6	TSL:1	c.931-1073C>T		intron	N/A	ENSP00000231803.1	P22607-3

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152228 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0365

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00276 AC: 693 AN: 250836 AF XY: 0.00258

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0369

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000952 AC: 1392 AN: 1461740 Hom.: 23 Cov.: 33 AF XY: 0.000906 AC XY: 659 AN XY: 727184

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0323 AC: 1283 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111996

Other (OTH) AF: 0.000927 AC: 56 AN: 60386

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152346 Hom.: 4 Cov.: 34 AF XY: 0.00150 AC XY: 112 AN XY: 74494

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0369 AC: 191 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.00147

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.4
DANN	Benign	0.93
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism

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: rs2305185; hg19: chr4-1805478; COSMIC: COSV53398862; COSMIC: COSV53398862;