5-177095415-C-A

Variant names:

• chr5-177095415-C-A
• rs1057519792
• NM_213647.3:c.1605C>A

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.1605C>A​(p.Asn535Lys) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR4 NM_213647.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 44 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, 0.918

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.1605C>A	p.Asn535Lys	missense	Exon 12 of 18	NP_998812.1
	FGFR4	NM_001354984.2		c.1605C>A	p.Asn535Lys	missense	Exon 12 of 18	NP_001341913.1
	FGFR4	NM_002011.5		c.1605C>A	p.Asn535Lys	missense	Exon 12 of 18	NP_002002.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR4	ENST00000292408.9	TSL:1 MANE Select	c.1605C>A	p.Asn535Lys	missense	Exon 12 of 18	ENSP00000292408.4
	FGFR4	ENST00000502906.5	TSL:1	c.1605C>A	p.Asn535Lys	missense	Exon 12 of 18	ENSP00000424960.1
	FGFR4	ENST00000393637.5	TSL:1	c.1485C>A	p.Asn495Lys	missense	Exon 10 of 16	ENSP00000377254.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.075
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.65	N
PhyloP100		1.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.79		Gain of methylation at N535 (P = 0.0173)
MVP		0.91
MPC		1.0
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.46
Mutation Taster		=63/37	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1057519792; hg19: chr5-176522416; COSMIC: COSV52801581; COSMIC: COSV52801581;