5-177090796-C-T

Position:

chr5-177090796-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_213647.3(FGFR4):c.407C>T(p.Pro136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,613,588 control chromosomes in the GnomAD database, including 481,410 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.75 ( 42815 hom., cov: 31)

Exomes 𝑓: 0.77 ( 438595 hom. )

Consequence

FGFR4
NM_213647.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.52

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:

FGFR4 (HGNC:):

FGFR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.291212E-7).

BP6

Variant 5-177090796-C-T is Benign according to our data. Variant chr5-177090796-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1679938.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.407C>T	p.Pro136Leu	missense_variant	4/18	ENST00000292408.9	NP_998812.1	P22455-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR4	ENST00000292408.9 linkuse as main transcript	c.407C>T	p.Pro136Leu	missense_variant	4/18	1	NM_213647.3	ENSP00000292408.4		P22455-1

Frequencies

GnomAD3 genomes

AF:

0.746

AC:

113370

AN:

151876

Hom.:

42756

Cov.:

show subpopulations

Gnomad AFR

AF:

0.661

Gnomad AMI

AF:

0.704

Gnomad AMR

AF:

0.788

Gnomad ASJ

AF:

0.767

Gnomad EAS

AF:

0.998

Gnomad SAS

AF:

0.893

Gnomad FIN

AF:

0.818

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.748

Gnomad OTH

AF:

0.743

GnomAD3 exomes

AF:

0.801

AC:

201070

AN:

251148

Hom.:

81471

AF XY:

0.802

AC XY:

108830

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.652

Gnomad AMR exome

AF:

0.863

Gnomad ASJ exome

AF:

0.755

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.885

Gnomad FIN exome

AF:

0.813

Gnomad NFE exome

AF:

0.751

Gnomad OTH exome

AF:

0.778

GnomAD4 exome

AF:

0.772

AC:

1128836

AN:

1461594

Hom.:

438595

Cov.:

AF XY:

0.774

AC XY:

563070

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.661

Gnomad4 AMR exome

AF:

0.856

Gnomad4 ASJ exome

AF:

0.755

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.879

Gnomad4 FIN exome

AF:

0.811

Gnomad4 NFE exome

AF:

0.755

Gnomad4 OTH exome

AF:

0.776

GnomAD4 genome

AF:

0.747

AC:

113490

AN:

151994

Hom.:

42815

Cov.:

AF XY:

0.753

AC XY:

55975

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.661

Gnomad4 AMR

AF:

0.788

Gnomad4 ASJ

AF:

0.767

Gnomad4 EAS

AF:

0.998

Gnomad4 SAS

AF:

0.893

Gnomad4 FIN

AF:

0.818

Gnomad4 NFE

AF:

0.748

Gnomad4 OTH

AF:

0.747

Alfa

AF:

0.750

Hom.:

108391

Bravo

AF:

0.739

TwinsUK

AF:

0.752

AC:

2789

ALSPAC

AF:

0.771

AC:

2970

ESP6500AA

AF:

0.661

AC:

2911

ESP6500EA

AF:

0.752

AC:

6467

ExAC

AF:

0.795

AC:

96483

Asia WGS

AF:

0.926

AC:

3221

AN:

3478

EpiCase

AF:

0.733

EpiControl

AF:

0.740

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Classic Hodgkin lymphoma

Benign:1

Likely benign, criteria provided, single submitter

research

Pathology Department, Puerta del Mar University Hospital

Oct 01, 2021

- -

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

0.068

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

8.0

DANN

Benign

0.32

DEOGEN2

Benign

0.30

T;T;.;T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.54

.;T;T;T;T

MetaRNN

Benign

9.3e-7

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;.;.;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

0.20

N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.33

T;T;T;T;T

Sift4G

Benign

0.32

T;T;T;T;T

Polyphen

0.0

B;B;.;B;B

Vest4

0.036

MPC

0.28

ClinPred

0.0033

GERP RS

2.9

Varity_R

0.026

gMVP

0.36

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