rs1966265

chr5-177089630-G-Achr5-177089630-G-Cchr5-177089630-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_213647.3(FGFR4):c.28G>A(p.Val10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,613,302 control chromosomes in the GnomAD database, including 50,228 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.19 ( 3672 hom., cov: 32)

Exomes 𝑓: 0.24 ( 46556 hom. )

Consequence

FGFR4
NM_213647.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.547

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.772808E-4).

BP6

Variant 5-177089630-G-A is Benign according to our data. Variant chr5-177089630-G-A is described in ClinVar as [Benign]. Clinvar id is 1291710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR4	NM_213647.3 linkuse as main transcript	c.28G>A	p.Val10Ile	missense_variant	2/18	ENST00000292408.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR4	ENST00000292408.9 linkuse as main transcript	c.28G>A	p.Val10Ile	missense_variant	2/18	1	NM_213647.3	P2	P22455-1

Frequencies

GnomAD3 genomes

AF:

0.193

AC:

29302

AN:

151966

Hom.:

3672

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0547

Gnomad AMI

AF:

0.259

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.519

Gnomad SAS

AF:

0.236

Gnomad FIN

AF:

0.230

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.177

GnomAD3 exomes

AF:

0.246

AC:

61443

AN:

249458

Hom.:

8861

AF XY:

0.243

AC XY:

32793

AN XY:

134954

show subpopulations

Gnomad AFR exome

AF:

0.0509

Gnomad AMR exome

AF:

0.319

Gnomad ASJ exome

AF:

0.159

Gnomad EAS exome

AF:

0.518

Gnomad SAS exome

AF:

0.220

Gnomad FIN exome

AF:

0.237

Gnomad NFE exome

AF:

0.227

Gnomad OTH exome

AF:

0.213

GnomAD4 exome

AF:

0.243

AC:

355547

AN:

1461218

Hom.:

46556

Cov.:

AF XY:

0.242

AC XY:

175842

AN XY:

726902

show subpopulations

Gnomad4 AFR exome

AF:

0.0446

Gnomad4 AMR exome

AF:

0.313

Gnomad4 ASJ exome

AF:

0.158

Gnomad4 EAS exome

AF:

0.537

Gnomad4 SAS exome

AF:

0.220

Gnomad4 FIN exome

AF:

0.229

Gnomad4 NFE exome

AF:

0.242

Gnomad4 OTH exome

AF:

0.228

GnomAD4 genome

AF:

0.193

AC:

29307

AN:

152084

Hom.:

3672

Cov.:

AF XY:

0.198

AC XY:

14728

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0545

Gnomad4 AMR

AF:

0.257

Gnomad4 ASJ

AF:

0.170

Gnomad4 EAS

AF:

0.519

Gnomad4 SAS

AF:

0.236

Gnomad4 FIN

AF:

0.230

Gnomad4 NFE

AF:

0.230

Gnomad4 OTH

AF:

0.179

Alfa

AF:

0.224

Hom.:

9193

Bravo

AF:

0.192

TwinsUK

AF:

0.240

AC:

891

ALSPAC

AF:

0.249

AC:

961

ESP6500AA

AF:

0.0611

AC:

269

ESP6500EA

AF:

0.227

AC:

1952

ExAC

AF:

0.236

AC:

28653

Asia WGS

AF:

0.307

AC:

1071

AN:

3476

EpiCase

AF:

0.213

EpiControl

AF:

0.213

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

FGFR4-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2020

This variant is associated with the following publications: (PMID: 24200957) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

Cadd

Benign

0.80

Dann

Benign

0.38

DEOGEN2

Benign

0.28

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

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.34

MetaRNN

Benign

0.00028

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

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

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

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.16

N;N;N;N;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.42

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

Sift4G

Benign

0.46

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

Polyphen

0.0

B;B;.;.;B;.;.;B

Vest4

0.065

MPC

0.22

ClinPred

0.0015

GERP RS

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.015

gMVP

0.18

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