NM_213647.3:c.407C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

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

Publications

80 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
FGFR4	NM_213647.3 link	c.407C>T	p.Pro136Leu	missense_variant	Exon 4 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.407C>T	p.Pro136Leu	missense_variant	Exon 4 of 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

GnomAD2 exomes

AF:

0.801

AC:

201070

AN:

251148

AF XY:

0.802

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 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

African (AFR)

AF:

0.661

AC:

22129

AN:

33476

American (AMR)

AF:

0.856

AC:

38264

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.755

AC:

19728

AN:

26114

East Asian (EAS)

AF:

0.999

AC:

39673

AN:

39700

South Asian (SAS)

AF:

0.879

AC:

75788

AN:

86250

European-Finnish (FIN)

AF:

0.811

AC:

43311

AN:

53404

Middle Eastern (MID)

AF:

0.691

AC:

3985

AN:

5768

European-Non Finnish (NFE)

AF:

0.755

AC:

839078

AN:

1111798

Other (OTH)

AF:

0.776

AC:

46880

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

14078

28156

42235

56313

70391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.747

AC:

113490

AN:

151994

Hom.:

42815

Cov.:

AF XY:

0.753

AC XY:

55975

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.661

AC:

27382

AN:

41398

American (AMR)

AF:

0.788

AC:

12033

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.767

AC:

2661

AN:

3470

East Asian (EAS)

AF:

0.998

AC:

5166

AN:

5174

South Asian (SAS)

AF:

0.893

AC:

4310

AN:

4824

European-Finnish (FIN)

AF:

0.818

AC:

8657

AN:

10584

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.748

AC:

50860

AN:

67966

Other (OTH)

AF:

0.747

AC:

1576

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1440

2879

4319

5758

7198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.749

Hom.:

150989

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

Oct 01, 2021

Pathology Department, Puerta del Mar University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

FGFR4-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

1.5

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

Mutation Taster

=96/4

polymorphism (auto)

(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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NM_213647.3:c.407C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over