4-1806181-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_000142.5(FGFR3):c.1959+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,612,668 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: FGFR3 NM_000142.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002509
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0770

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-1806181-C-T is Benign according to our data. Variant chr4-1806181-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1806181-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000551 (84/152336) while in subpopulation SAS AF= 0.00352 (17/4830). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR3	NM_000142.5	c.1959+8C>T		splice_region_variant, intron_variant		ENST00000440486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR3	ENST00000440486.8	c.1959+8C>T		splice_region_variant, intron_variant		5	NM_000142.5	P4

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000786 AC: 195 AN: 248042 Hom.: 1 AF XY: 0.000853 AC XY: 115 AN XY: 134846

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.0000933

Gnomad NFE exome AF: 0.000798

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000696 AC: 1016 AN: 1460332 Hom.: 1 Cov.: 38 AF XY: 0.000734 AC XY: 533 AN XY: 726472

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.000171

Gnomad4 NFE exome AF: 0.000676

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.000443 AC XY: 33 AN XY: 74480

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000625 Hom.: 0

Bravo AF: 0.000484

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.3
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
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: rs371666188; hg19: chr4-1807908;