5-177092286-G-A

Variant names:

• chr5-177092286-G-A
• rs393923
• NM_213647.3:c.728-35G>A

Variant summary

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

The NM_213647.3(FGFR4):​c.728-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,505,656 control chromosomes in the GnomAD database, including 494,444 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 0.84 (53485 hom., cov: 31)
  • Exomes 𝑓: 0.81 (440959 hom.)
• Consequence: FGFR4 NM_213647.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.863
• Publications: 11 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213647.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR4	NM_213647.3	MANE Select	c.728-35G>A		intron	N/A	NP_998812.1
	FGFR4	NM_001354984.2		c.728-35G>A		intron	N/A	NP_001341913.1
	FGFR4	NM_002011.5		c.728-35G>A		intron	N/A	NP_002002.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR4	ENST00000292408.9	TSL:1 MANE Select	c.728-35G>A		intron	N/A	ENSP00000292408.4
	FGFR4	ENST00000502906.5	TSL:1	c.728-35G>A		intron	N/A	ENSP00000424960.1
	FGFR4	ENST00000393637.5	TSL:1	c.728-35G>A		intron	N/A	ENSP00000377254.1

Frequencies

GnomAD3 genomes AF: 0.835 AC: 127007 AN: 152036 Hom.: 53419 Cov.: 31

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.929

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.809

GnomAD2 exomes AF: 0.842 AC: 148656 AN: 176506 AF XY: 0.839

Gnomad AFR exome AF: 0.908

Gnomad AMR exome AF: 0.878

Gnomad ASJ exome AF: 0.776

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.848

Gnomad NFE exome AF: 0.782

Gnomad OTH exome AF: 0.811

GnomAD4 exome AF: 0.805 AC: 1089962 AN: 1353502 Hom.: 440959 Cov.: 33 AF XY: 0.807 AC XY: 533977 AN XY: 661950

African (AFR) AF: 0.905 AC: 27412 AN: 30292

American (AMR) AF: 0.872 AC: 25677 AN: 29434

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 15614 AN: 20004

East Asian (EAS) AF: 1.00 AC: 38000 AN: 38014

South Asian (SAS) AF: 0.916 AC: 63944 AN: 69800

European-Finnish (FIN) AF: 0.844 AC: 41523 AN: 49182

Middle Eastern (MID) AF: 0.747 AC: 3048 AN: 4078

European-Non Finnish (NFE) AF: 0.785 AC: 829374 AN: 1057084

Other (OTH) AF: 0.816 AC: 45370 AN: 55614

GnomAD4 genome AF: 0.836 AC: 127132 AN: 152154 Hom.: 53485 Cov.: 31 AF XY: 0.839 AC XY: 62451 AN XY: 74392

African (AFR) AF: 0.902 AC: 37434 AN: 41516

American (AMR) AF: 0.828 AC: 12657 AN: 15292

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

East Asian (EAS) AF: 0.999 AC: 5159 AN: 5164

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

European-Finnish (FIN) AF: 0.849 AC: 9004 AN: 10604

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53052 AN: 67964

Other (OTH) AF: 0.812 AC: 1710 AN: 2106

Alfa AF: 0.816 Hom.: 20028

Bravo AF: 0.835

Asia WGS AF: 0.958 AC: 3331 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.21
DANN	Benign	0.66
PhyloP100		-0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs393923; hg19: chr5-176519287;