rs351855

Positions:

chr5-177093242-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000292408.9(FGFR4):c.1162G>A(p.Gly388Arg) variant causes a missense change. The variant allele was found at a frequency of 0.303 in 1,612,462 control chromosomes in the GnomAD database, including 76,363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.27 ( 6207 hom., cov: 33)

Exomes 𝑓: 0.31 ( 70156 hom. )

Consequence

FGFR4
ENST00000292408.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:2

Conservation

PhyloP100: 6.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041104257).

BP6

Variant 5-177093242-G-A is Benign according to our data. Variant chr5-177093242-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16326.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR4	NM_213647.3 linkuse as main transcript	c.1162G>A	p.Gly388Arg	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 linkuse as main transcript	c.1162G>A	p.Gly388Arg	missense_variant	9/18	1	NM_213647.3	ENSP00000292408	P2	P22455-1

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40763

AN:

151936

Hom.:

6207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.272

Gnomad AMR

AF:

0.330

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.449

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.325

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.305

Gnomad OTH

AF:

0.270

GnomAD3 exomes

AF:

0.327

AC:

80930

AN:

247408

Hom.:

14006

AF XY:

0.325

AC XY:

43607

AN XY:

134080

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.420

Gnomad ASJ exome

AF:

0.320

Gnomad EAS exome

AF:

0.450

Gnomad SAS exome

AF:

0.352

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.318

GnomAD4 exome

AF:

0.306

AC:

447158

AN:

1460408

Hom.:

70156

Cov.:

AF XY:

0.307

AC XY:

223241

AN XY:

726378

show subpopulations

Gnomad4 AFR exome

AF:

0.129

Gnomad4 AMR exome

AF:

0.407

Gnomad4 ASJ exome

AF:

0.316

Gnomad4 EAS exome

AF:

0.437

Gnomad4 SAS exome

AF:

0.350

Gnomad4 FIN exome

AF:

0.329

Gnomad4 NFE exome

AF:

0.298

Gnomad4 OTH exome

AF:

0.309

GnomAD4 genome

AF:

0.268

AC:

40785

AN:

152054

Hom.:

6207

Cov.:

AF XY:

0.272

AC XY:

20216

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.133

Gnomad4 AMR

AF:

0.330

Gnomad4 ASJ

AF:

0.321

Gnomad4 EAS

AF:

0.449

Gnomad4 SAS

AF:

0.366

Gnomad4 FIN

AF:

0.325

Gnomad4 NFE

AF:

0.305

Gnomad4 OTH

AF:

0.272

Alfa

AF:

0.299

Hom.:

9580

Bravo

AF:

0.263

TwinsUK

AF:

0.297

AC:

1101

ALSPAC

AF:

0.291

AC:

1120

ESP6500AA

AF:

0.129

AC:

567

ESP6500EA

AF:

0.301

AC:

2583

ExAC

AF:

0.317

AC:

38447

Asia WGS

AF:

0.400

AC:

1386

AN:

3476

EpiCase

AF:

0.298

EpiControl

AF:

0.301

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cancer progression and tumor cell motility

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2002

- -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 17, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply. -

not specified

Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.172, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

FGFR4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.63

.;T

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.018

P;P;P;P;P

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.16

N;N

REVEL

Uncertain

0.52

Sift

Benign

0.12

T;T

Sift4G

Benign

0.36

T;T

Polyphen

1.0

D;D

Vest4

0.47

MutPred

0.26

Gain of MoRF binding (P = 0.0102);Gain of MoRF binding (P = 0.0102);

MPC

0.83

ClinPred

0.018

GERP RS

4.3

BranchPoint Hunter

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over