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

Variant summary

Our verdict is Benign. Variant got -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 made for transcript

Verdict is Benign. Variant got -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

GnomAD3 exomes

AF:

0.772

AC:

186567

AN:

241800

Hom.:

73200

AF XY:

0.774

AC XY:

101659

AN XY:

131274

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 SAS exome

AF:

0.893

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

Gnomad4 AFR exome

AF:

0.609

Gnomad4 AMR exome

AF:

0.834

Gnomad4 ASJ exome

AF:

0.715

Gnomad4 EAS exome

AF:

0.978

Gnomad4 SAS exome

AF:

0.888

Gnomad4 FIN exome

AF:

0.755

Gnomad4 NFE exome

AF:

0.724

Gnomad4 OTH exome

AF:

0.743

GnomAD4 genome

AF:

0.712

AC:

108224

AN:

152060

Hom.:

39083

Cov.:

AF XY:

0.718

AC XY:

53389

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.612

Gnomad4 AMR

AF:

0.754

Gnomad4 ASJ

AF:

0.726

Gnomad4 EAS

AF:

0.976

Gnomad4 SAS

AF:

0.900

Gnomad4 FIN

AF:

0.761

Gnomad4 NFE

AF:

0.722

Gnomad4 OTH

AF:

0.702

Alfa

AF:

0.715

Hom.:

9639

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

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