rs434434

Positions:

• chr5-177089952-A-G

Variant summary

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

The NM_213647.3(FGFR4):​c.91+259A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 688,110 control chromosomes in the GnomAD database, including 228,865 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 0.79 (47992 hom., cov: 31)
  • Exomes 𝑓: 0.82 (180873 hom.)
• Consequence: FGFR4 NM_213647.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07

Genes affected

FGFR4 (HGNC:3691): (fibroblast growth factor receptor 4) The protein encoded by this gene is a tyrosine kinase and cell surface receptor for fibroblast growth factors. The encoded protein is involved in the regulation of several pathways, including cell proliferation, cell differentiation, cell migration, lipid metabolism, bile acid biosynthesis, vitamin D metabolism, glucose uptake, and phosphate homeostasis. This protein consists 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 interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR4	NM_213647.3	c.91+259A>G		intron_variant		ENST00000292408.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR4	ENST00000292408.9	c.91+259A>G		intron_variant		1	NM_213647.3	P2

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120394 AN: 151968 Hom.: 47933 Cov.: 31

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.929

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.778

GnomAD3 exomes AF: 0.841 AC: 109362 AN: 129990 Hom.: 46382 AF XY: 0.844 AC XY: 59798 AN XY: 70838

Gnomad AFR exome AF: 0.739

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.784

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.920

Gnomad FIN exome AF: 0.841

Gnomad NFE exome AF: 0.780

Gnomad OTH exome AF: 0.806

GnomAD4 exome AF: 0.818 AC: 438676 AN: 536024 Hom.: 180873 Cov.: 4 AF XY: 0.823 AC XY: 238780 AN XY: 290302

Gnomad4 AFR exome AF: 0.753

Gnomad4 AMR exome AF: 0.867

Gnomad4 ASJ exome AF: 0.782

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.915

Gnomad4 FIN exome AF: 0.843

Gnomad4 NFE exome AF: 0.781

Gnomad4 OTH exome AF: 0.805

GnomAD4 genome AF: 0.792 AC: 120512 AN: 152086 Hom.: 47992 Cov.: 31 AF XY: 0.798 AC XY: 59321 AN XY: 74356

Gnomad4 AFR AF: 0.751

Gnomad4 AMR AF: 0.812

Gnomad4 ASJ AF: 0.790

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.929

Gnomad4 FIN AF: 0.849

Gnomad4 NFE AF: 0.780

Gnomad4 OTH AF: 0.781

Alfa AF: 0.783 Hom.: 9528

Bravo AF: 0.785

Asia WGS AF: 0.951 AC: 3308 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	10
DANN	Benign	0.56

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: rs434434; hg19: chr5-176516953; COSMIC: COSV99448683; COSMIC: COSV99448683;