rs17883356

chr4-1806558-G-Achr4-1806558-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PM1 PM2 BP4_Strong BP6_Very_Strong BS1

The ENST00000481110.7(FGFR3):c.1975G>A(p.Gly659Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,612,948 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: FGFR3 ENST00000481110.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.147

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000481110.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014253825).
• BP6: Variant 4-1806558-G-A is Benign according to our data. Variant chr4-1806558-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 465352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000894 (136/152108) while in subpopulation AFR AF= 0.00328 (136/41490). AF 95% confidence interval is 0.00283. There are 1 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.2043G>A	p.Gly681=	synonymous_variant	16/18	ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.2043G>A	p.Gly681=	synonymous_variant	16/18	5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.000888 AC: 135 AN: 151990 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000208 AC: 52 AN: 250366 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135758

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000856 AC: 125 AN: 1460840 Hom.: 0 Cov.: 39 AF XY: 0.0000729 AC XY: 53 AN XY: 726708

Gnomad4 AFR exome AF: 0.00329

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000894 AC: 136 AN: 152108 Hom.: 1 Cov.: 33 AF XY: 0.000901 AC XY: 67 AN XY: 74358

Gnomad4 AFR AF: 0.00328

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000926

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	6.9
Dann	Benign	0.94
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.41	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D;D;D;N
PROVEAN	Benign	0.40	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.32
MVP		0.90
ClinPred		0.48	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs17883356; hg19: chr4-1808285;