rs1057520036

chr5-177093180-A-Cchr5-177093180-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_213647.3(FGFR4):c.1100A>C(p.Tyr367Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. Y367C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR4 NM_213647.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.81

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-177093180-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376737.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34413525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR4	NM_213647.3	c.1100A>C	p.Tyr367Ser	missense_variant	9/18	ENST00000292408.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR4	ENST00000292408.9	c.1100A>C	p.Tyr367Ser	missense_variant	9/18	1	NM_213647.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	20
Dann	Benign	0.95
DEOGEN2	Uncertain	0.79	D;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	0.017	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.42
Sift	Benign	0.053	T;T
Sift4G	Uncertain	0.046	D;D
Polyphen		0.016	B;B
Vest4		0.31
MutPred		0.58		Gain of glycosylation at Y367 (P = 0.0045);Gain of glycosylation at Y367 (P = 0.0045);
MVP		0.95
MPC		0.40
ClinPred		0.66	D
GERP RS		2.6
Varity_R		0.37
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-176520181;