4-1793812-GCTGCCTTC-G

Variant names:

• chr4-1793812-GCTGCCTTC-G
• rs1452696194
• NM_000142.5:c.-102-18_-102-11delGCCTTCCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000142.5(FGFR3):​c.-102-18_-102-11delGCCTTCCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00677 in 177,748 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.849
• 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: 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)

ENSG00000305534 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 4-1793812-GCTGCCTTC-G is Benign according to our data. Variant chr4-1793812-GCTGCCTTC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1229898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00595 (886/148874) while in subpopulation NFE AF = 0.00873 (581/66554). AF 95% confidence interval is 0.00814. There are 8 homozygotes in GnomAd4. There are 416 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR,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.-102-18_-102-11delGCCTTCCT		intron	N/A	NP_000133.1	P22607-1
	FGFR3	NM_001163213.2		c.-102-18_-102-11delGCCTTCCT		intron	N/A	NP_001156685.1	P22607-2
	FGFR3	NM_001354809.2		c.-102-18_-102-11delGCCTTCCT		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.-102-18_-102-11delGCCTTCCT		intron	N/A	ENSP00000414914.2	P22607-1
	FGFR3	ENST00000481110.7	TSL:1	c.-102-18_-102-11delGCCTTCCT		intron	N/A	ENSP00000420533.2	F8W9L4
	FGFR3	ENST00000260795.8	TSL:1	n.-102-18_-102-11delGCCTTCCT		intron	N/A	ENSP00000260795.3	I6LM06

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 885 AN: 148766 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00168

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00593

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00696

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00873

Gnomad OTH AF: 0.00877

GnomAD4 exome AF: 0.0110 AC: 317 AN: 28874 Hom.: 0 AF XY: 0.0112 AC XY: 175 AN XY: 15572

African (AFR) AF: 0.00 AC: 0 AN: 500

American (AMR) AF: 0.00326 AC: 2 AN: 614

Ashkenazi Jewish (ASJ) AF: 0.00957 AC: 4 AN: 418

East Asian (EAS) AF: 0.00 AC: 0 AN: 634

South Asian (SAS) AF: 0.00 AC: 0 AN: 1028

European-Finnish (FIN) AF: 0.0101 AC: 19 AN: 1874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 110

European-Non Finnish (NFE) AF: 0.0125 AC: 280 AN: 22324

Other (OTH) AF: 0.00875 AC: 12 AN: 1372

GnomAD4 genome AF: 0.00595 AC: 886 AN: 148874 Hom.: 8 Cov.: 32 AF XY: 0.00573 AC XY: 416 AN XY: 72582

African (AFR) AF: 0.00168 AC: 69 AN: 41192

American (AMR) AF: 0.00592 AC: 89 AN: 15024

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 42 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.00696 AC: 66 AN: 9486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00873 AC: 581 AN: 66554

Other (OTH) AF: 0.00868 AC: 18 AN: 2074

Alfa AF: 0.00778 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1452696194; hg19: chr4-1795539;