dbSNP rs569265847: FGFR4:p.Arg85Gly (chr5-177090551-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_213647.3(FGFR4):c.253C>G(p.Arg85Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R85C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

FGFR4
NM_213647.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.256

Publications

0 publications found

Variant links:

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]

FGFR4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30778888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR4	NM_213647.3 link	c.253C>G	p.Arg85Gly	missense_variant	Exon 3 of 18	ENST00000292408.9	NP_998812.1	P22455-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR4	ENST00000292408.9 link	c.253C>G	p.Arg85Gly	missense_variant	Exon 3 of 18	1	NM_213647.3	ENSP00000292408.4		P22455-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1375748

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

675118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30626

American (AMR)

AF:

0.00

AC:

AN:

31066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20322

East Asian (EAS)

AF:

0.00

AC:

AN:

39020

South Asian (SAS)

AF:

0.00

AC:

AN:

71458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5344

European-Non Finnish (NFE)

AF:

9.33e-7

AC:

AN:

1071642

Other (OTH)

AF:

0.00

AC:

AN:

56586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;.;.;T;.;T;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.84

.;T;D;D;T;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.31

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.49

N;.;.;.;N;.;.;N

PhyloP100

0.26

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.7

N;D;N;N;N;D;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.28

T;T;T;T;T;D;T;T

Sift4G

Benign

0.33

T;T;T;D;T;D;D;T

Polyphen

0.83

P;D;.;.;P;.;.;D

Vest4

0.42

MutPred

0.39

Loss of methylation at R85 (P = 0.0165);Loss of methylation at R85 (P = 0.0165);Loss of methylation at R85 (P = 0.0165);Loss of methylation at R85 (P = 0.0165);Loss of methylation at R85 (P = 0.0165);Loss of methylation at R85 (P = 0.0165);Loss of methylation at R85 (P = 0.0165);Loss of methylation at R85 (P = 0.0165);

MVP

0.91

MPC

0.43

ClinPred

0.64

GERP RS

4.0

Varity_R

0.14

gMVP

0.77

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over