Genetic Variant FGFR4:p.Arg54Arg (chr5-177090460-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_213647.3(FGFR4):c.162T>G(p.Arg54Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 1,602,806 control chromosomes in the GnomAD database, including 443,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.71 ( 39083 hom., cov: 32)

Exomes 𝑓: 0.74 ( 403963 hom. )

Consequence

FGFR4
NM_213647.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.479

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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 5-177090460-T-G is Benign according to our data. Variant chr5-177090460-T-G is described in ClinVar as [Benign]. Clinvar id is 3061016.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.479 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR4	NM_213647.3 link	c.162T>G	p.Arg54Arg	synonymous_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.162T>G	p.Arg54Arg	synonymous_variant	Exon 3 of 18	1	NM_213647.3	ENSP00000292408.4		P22455-1

Frequencies

GnomAD3 genomes

AF:

0.712

AC:

108139

AN:

151942

Hom.:

39047

Cov.:

show subpopulations

Gnomad AFR

AF:

0.612

Gnomad AMI

AF:

0.699

Gnomad AMR

AF:

0.754

Gnomad ASJ

AF:

0.726

Gnomad EAS

AF:

0.976

Gnomad SAS

AF:

0.900

Gnomad FIN

AF:

0.761

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.722

Gnomad OTH

AF:

0.703

GnomAD2 exomes

AF:

0.772

AC:

186567

AN:

241800

AF XY:

0.774

show subpopulations

Gnomad AFR exome

AF:

0.604

Gnomad AMR exome

AF:

0.844

Gnomad ASJ exome

AF:

0.713

Gnomad EAS exome

AF:

0.972

Gnomad FIN exome

AF:

0.756

Gnomad NFE exome

AF:

0.717

Gnomad OTH exome

AF:

0.737

GnomAD4 exome

AF:

0.743

AC:

1078055

AN:

1450746

Hom.:

403963

Cov.:

AF XY:

0.747

AC XY:

538620

AN XY:

721374

show subpopulations

African (AFR)

AF:

0.609

AC:

20329

AN:

33408

American (AMR)

AF:

0.834

AC:

37009

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.715

AC:

18275

AN:

25550

East Asian (EAS)

AF:

0.978

AC:

38768

AN:

39630

South Asian (SAS)

AF:

0.888

AC:

75858

AN:

85400

European-Finnish (FIN)

AF:

0.755

AC:

36509

AN:

48336

Middle Eastern (MID)

AF:

0.662

AC:

3778

AN:

5704

European-Non Finnish (NFE)

AF:

0.724

AC:

802875

AN:

1108260

Other (OTH)

AF:

0.743

AC:

44654

AN:

60086

Heterozygous variant carriers

17366

34731

52097

69462

86828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

20074

40148

60222

80296

100370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.712

AC:

108224

AN:

152060

Hom.:

39083

Cov.:

AF XY:

0.718

AC XY:

53389

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.612

AC:

25369

AN:

41448

American (AMR)

AF:

0.754

AC:

11537

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.726

AC:

2518

AN:

3468

East Asian (EAS)

AF:

0.976

AC:

5044

AN:

5170

South Asian (SAS)

AF:

0.900

AC:

4342

AN:

4822

European-Finnish (FIN)

AF:

0.761

AC:

8051

AN:

10582

Middle Eastern (MID)

AF:

0.622

AC:

183

AN:

294

European-Non Finnish (NFE)

AF:

0.722

AC:

49065

AN:

67966

Other (OTH)

AF:

0.702

AC:

1479

AN:

2108

Heterozygous variant carriers

1568

3136

4705

6273

7841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.712

Hom.:

10754

Bravo

AF:

0.704

Asia WGS

AF:

0.883

AC:

3073

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.7

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

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