chr5-177093180-A-G

Position:

• chr5-177093180-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000292408.9(FGFR4):​c.1100A>G​(p.Tyr367Cys) 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. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR4 ENST00000292408.9 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• PP5: Variant 5-177093180-A-G is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR4	NM_213647.3	c.1100A>G	p.Tyr367Cys	missense_variant	9/18	ENST00000292408.9	NP_998812.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR4	ENST00000292408.9	c.1100A>G	p.Tyr367Cys	missense_variant	9/18	1	NM_213647.3	ENSP00000292408	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.97	D;D
Vest4		0.70
MutPred		0.53		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.96
MPC		0.88
ClinPred		0.99	D
GERP RS		2.6
Varity_R		0.40
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057520036; hg19: chr5-176520181; COSMIC: COSV52801727; COSMIC: COSV52801727;