rs3135889

chr4-1804314-G-Achr4-1804314-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000142.5(FGFR3):c.1076-16G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00345 in 1,587,218 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0035 (17 hom.)
• Consequence: FGFR3 NM_000142.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.582

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-1804314-G-A is Benign according to our data. Variant chr4-1804314-G-A is described in ClinVar as [Benign]. Clinvar id is 255325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1804314-G-A is described in Lovd as [Benign]. Variant chr4-1804314-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00286 (434/151984) while in subpopulation AMR AF= 0.00589 (90/15282). AF 95% confidence interval is 0.00491. There are 4 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.1076-16G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.1076-16G>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 434 AN: 151868 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00265 AC: 598 AN: 225904 Hom.: 6 AF XY: 0.00231 AC XY: 281 AN XY: 121624

Gnomad AFR exome AF: 0.000818

Gnomad AMR exome AF: 0.00505

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000384

Gnomad FIN exome AF: 0.00146

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00395

GnomAD4 exome AF: 0.00351 AC: 5043 AN: 1435234 Hom.: 17 Cov.: 36 AF XY: 0.00335 AC XY: 2386 AN XY: 711892

Gnomad4 AFR exome AF: 0.000754

Gnomad4 AMR exome AF: 0.00543

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000610

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.00408

Gnomad4 OTH exome AF: 0.00369

GnomAD4 genome AF: 0.00286 AC: 434 AN: 151984 Hom.: 4 Cov.: 34 AF XY: 0.00252 AC XY: 187 AN XY: 74310

Gnomad4 AFR AF: 0.000965

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00114

Gnomad4 NFE AF: 0.00416

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00265 Hom.: 1

Bravo AF: 0.00318

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.71
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3135889; hg19: chr4-1806041;