rs1784326239

Variant names:

• chr5-177090530-C-A
• rs1784326239
• NM_213647.3:c.232C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-177090530-C-A
• chr5-177090530-C-G
• chr5-177090530-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_213647.3(FGFR4):​c.232C>A​(p.Arg78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,403,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R78C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FGFR4 NM_213647.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.41
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR4	NM_213647.3	c.232C>A	p.Arg78Ser	missense_variant	Exon 3 of 18	ENST00000292408.9	NP_998812.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR4	ENST00000292408.9	c.232C>A	p.Arg78Ser	missense_variant	Exon 3 of 18	1	NM_213647.3	ENSP00000292408.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1403542 Hom.: 0 Cov.: 70 AF XY: 0.00000289 AC XY: 2 AN XY: 691400

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000312 AC: 1 AN: 32092

American (AMR) AF: 0.00 AC: 0 AN: 38124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39242

South Asian (SAS) AF: 0.00 AC: 0 AN: 75698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083018

Other (OTH) AF: 0.0000173 AC: 1 AN: 57894

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;T;.;.;D;.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M;.;.;M
PhyloP100		3.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		0.97	D;D;.;.;D;.;.;D
Vest4		0.84
MutPred		0.62		Gain of phosphorylation at R78 (P = 0.0241);Gain of phosphorylation at R78 (P = 0.0241);Gain of phosphorylation at R78 (P = 0.0241);Gain of phosphorylation at R78 (P = 0.0241);Gain of phosphorylation at R78 (P = 0.0241);Gain of phosphorylation at R78 (P = 0.0241);Gain of phosphorylation at R78 (P = 0.0241);Gain of phosphorylation at R78 (P = 0.0241);
MVP		0.96
MPC		0.86
ClinPred		0.98	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.35
gMVP		0.74
Mutation Taster		=58/42	polymorphism

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: rs1784326239; hg19: chr5-176517531;