chr4-1801580-T-C

Variant names:

• chr4-1801580-T-C
• rs2305183
• NM_000142.5:c.616-40T>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.616-40T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,583,716 control chromosomes in the GnomAD database, including 23,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4667 hom., cov: 34)
  • Exomes 𝑓: 0.15 (18474 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.892
• Publications: 12 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=-0.93).
• BP6: Variant 4-1801580-T-C is Benign according to our data. Variant chr4-1801580-T-C is described in ClinVar as Benign. ClinVar VariationId is 255343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.616-40T>C		intron_variant	Intron 5 of 17	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.616-40T>C		intron_variant	Intron 5 of 17	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32612 AN: 152088 Hom.: 4637 Cov.: 34

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.0662

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.160 AC: 31080 AN: 193970 AF XY: 0.160

Gnomad AFR exome AF: 0.403

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.0425

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.152 AC: 217972 AN: 1431510 Hom.: 18474 Cov.: 39 AF XY: 0.154 AC XY: 109056 AN XY: 709838

African (AFR) AF: 0.417 AC: 13718 AN: 32908

American (AMR) AF: 0.128 AC: 5115 AN: 39962

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5711 AN: 25538

East Asian (EAS) AF: 0.0942 AC: 3580 AN: 38010

South Asian (SAS) AF: 0.212 AC: 17525 AN: 82818

European-Finnish (FIN) AF: 0.135 AC: 6640 AN: 49012

Middle Eastern (MID) AF: 0.249 AC: 1427 AN: 5722

European-Non Finnish (NFE) AF: 0.140 AC: 154148 AN: 1098312

Other (OTH) AF: 0.171 AC: 10108 AN: 59228

GnomAD4 genome AF: 0.215 AC: 32699 AN: 152206 Hom.: 4667 Cov.: 34 AF XY: 0.211 AC XY: 15722 AN XY: 74434

African (AFR) AF: 0.404 AC: 16759 AN: 41512

American (AMR) AF: 0.147 AC: 2246 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 740 AN: 3468

East Asian (EAS) AF: 0.0664 AC: 344 AN: 5182

South Asian (SAS) AF: 0.203 AC: 980 AN: 4832

European-Finnish (FIN) AF: 0.131 AC: 1389 AN: 10622

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9632 AN: 67980

Other (OTH) AF: 0.209 AC: 442 AN: 2116

Alfa AF: 0.125 Hom.: 292

Bravo AF: 0.226

Asia WGS AF: 0.181 AC: 629 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.39
DANN	Benign	0.12
PhyloP100		-0.89
PromoterAI		-0.036	Neutral
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)		0.0		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: rs2305183; hg19: chr4-1803307; COSMIC: COSV53402151; COSMIC: COSV53402151;