rs3135848

Variant names:

• chr4-1796014-T-C
• rs3135848
• NM_000142.5:c.109+1971T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000142.5(FGFR3):​c.109+1971T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 152,132 control chromosomes in the GnomAD database, including 14,995 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (14995 hom., cov: 32)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.418

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR3	NM_000142.5	c.109+1971T>C		intron_variant	Intron 2 of 17	ENST00000440486.8	NP_000133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR3	ENST00000440486.8	c.109+1971T>C		intron_variant	Intron 2 of 17	5	NM_000142.5	ENSP00000414914.2

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60830 AN: 152014 Hom.: 14956 Cov.: 32

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.391

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.400 AC: 60915 AN: 152132 Hom.: 14995 Cov.: 32 AF XY: 0.396 AC XY: 29441 AN XY: 74382

Gnomad4 AFR AF: 0.702

Gnomad4 AMR AF: 0.348

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.251

Gnomad4 NFE AF: 0.282

Gnomad4 OTH AF: 0.388

Alfa AF: 0.321 Hom.: 6604

Bravo AF: 0.421

Asia WGS AF: 0.262 AC: 911 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.3
DANN	Benign	0.72

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: rs3135848; hg19: chr4-1797741;