4-1803866-G-C

Variant names:

• chr4-1803866-G-C
• rs3135886
• NM_000142.5:c.1075+30G>C

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.1075+30G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 1,605,042 control chromosomes in the GnomAD database, including 2,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (134 hom., cov: 34)
  • Exomes 𝑓: 0.051 (2113 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.21
• Publications: 5 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=-0.82).
• BP6: Variant 4-1803866-G-C is Benign according to our data. Variant chr4-1803866-G-C is described in ClinVar as Benign. ClinVar VariationId is 255322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0528 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.1075+30G>C		intron	N/A	NP_000133.1
	FGFR3	NM_001163213.2		c.1082-464G>C		intron	N/A	NP_001156685.1
	FGFR3	NM_001354809.2		c.1075+30G>C		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.1075+30G>C		intron	N/A	ENSP00000414914.2
	FGFR3	ENST00000481110.7	TSL:1	c.1075+30G>C		intron	N/A	ENSP00000420533.2
	FGFR3	ENST00000352904.6	TSL:1	c.931-958G>C		intron	N/A	ENSP00000231803.1

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5611 AN: 152200 Hom.: 134 Cov.: 34

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0543

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0371 AC: 9260 AN: 249742 AF XY: 0.0380

Gnomad AFR exome AF: 0.00867

Gnomad AMR exome AF: 0.0271

Gnomad ASJ exome AF: 0.0696

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0337

Gnomad NFE exome AF: 0.0548

Gnomad OTH exome AF: 0.0493

GnomAD4 exome AF: 0.0505 AC: 73417 AN: 1452724 Hom.: 2113 Cov.: 30 AF XY: 0.0498 AC XY: 35994 AN XY: 723226

African (AFR) AF: 0.00894 AC: 298 AN: 33328

American (AMR) AF: 0.0285 AC: 1275 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 1789 AN: 26072

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39646

South Asian (SAS) AF: 0.00984 AC: 847 AN: 86100

European-Finnish (FIN) AF: 0.0339 AC: 1771 AN: 52280

Middle Eastern (MID) AF: 0.0596 AC: 337 AN: 5656

European-Non Finnish (NFE) AF: 0.0581 AC: 64246 AN: 1104834

Other (OTH) AF: 0.0474 AC: 2850 AN: 60108

GnomAD4 genome AF: 0.0368 AC: 5609 AN: 152318 Hom.: 134 Cov.: 34 AF XY: 0.0348 AC XY: 2594 AN XY: 74482

African (AFR) AF: 0.0103 AC: 429 AN: 41560

American (AMR) AF: 0.0395 AC: 605 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 245 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.00931 AC: 45 AN: 4832

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10614

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0543 AC: 3693 AN: 68034

Other (OTH) AF: 0.0402 AC: 85 AN: 2114

Alfa AF: 0.0244 Hom.: 16

Bravo AF: 0.0371

Asia WGS AF: 0.00635 AC: 23 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	-0.82
CADD	Benign	7.3
DANN	Benign	0.51
PhyloP100		1.2
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: rs3135886; hg19: chr4-1805593; COSMIC: COSV53410982;