chr5-177090325-T-C

Variant names:

• chr5-177090325-T-C
• rs422421
• NM_213647.3:c.92-65T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_213647.3(FGFR4):​c.92-65T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,597,734 control chromosomes in the GnomAD database, including 515,598 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 (48000 hom., cov: 33)
  • Exomes 𝑓: 0.80 (467598 hom.)
• Consequence: FGFR4 NM_213647.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.159
• Publications: 59 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• 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 rank	MANE	Protein	UniProt
FGFR4	NM_213647.3	c.92-65T>C		intron_variant	Intron 2 of 17	ENST00000292408.9	NP_998812.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR4	ENST00000292408.9	c.92-65T>C		intron_variant	Intron 2 of 17	1	NM_213647.3	ENSP00000292408.4

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120426 AN: 152042 Hom.: 47941 Cov.: 33

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.928

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.779

GnomAD2 exomes AF: 0.833 AC: 192963 AN: 231708 AF XY: 0.833

Gnomad AFR exome AF: 0.748

Gnomad AMR exome AF: 0.879

Gnomad ASJ exome AF: 0.783

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.782

Gnomad OTH exome AF: 0.805

GnomAD4 exome AF: 0.802 AC: 1159945 AN: 1445574 Hom.: 467598 Cov.: 38 AF XY: 0.805 AC XY: 579004 AN XY: 719554

African (AFR) AF: 0.753 AC: 25205 AN: 33460

American (AMR) AF: 0.872 AC: 38987 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20423 AN: 26130

East Asian (EAS) AF: 1.00 AC: 39676 AN: 39694

South Asian (SAS) AF: 0.915 AC: 78684 AN: 85950

European-Finnish (FIN) AF: 0.843 AC: 32616 AN: 38704

Middle Eastern (MID) AF: 0.743 AC: 4284 AN: 5764

European-Non Finnish (NFE) AF: 0.784 AC: 871391 AN: 1110906

Other (OTH) AF: 0.808 AC: 48679 AN: 60270

GnomAD4 genome AF: 0.792 AC: 120544 AN: 152160 Hom.: 48000 Cov.: 33 AF XY: 0.798 AC XY: 59317 AN XY: 74378

African (AFR) AF: 0.751 AC: 31182 AN: 41504

American (AMR) AF: 0.811 AC: 12395 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.790 AC: 2742 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5171 AN: 5176

South Asian (SAS) AF: 0.929 AC: 4486 AN: 4830

European-Finnish (FIN) AF: 0.849 AC: 9012 AN: 10618

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.780 AC: 53022 AN: 67970

Other (OTH) AF: 0.782 AC: 1648 AN: 2108

Alfa AF: 0.788 Hom.: 161728

Bravo AF: 0.785

Asia WGS AF: 0.951 AC: 3309 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.7
DANN	Benign	0.62
PhyloP100		-0.16
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs422421; hg19: chr5-176517326; COSMIC: COSV99448695;