5-177092323-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_213647.3(FGFR4):c.730C>T(p.Arg244Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000765 in 1,569,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

FGFR4
NM_213647.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213647.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGFR4	NM_213647.3	MANE Select	c.730C>T	p.Arg244Trp	missense splice_region	Exon 7 of 18	NP_998812.1	P22455-1
FGFR4	NM_001354984.2		c.730C>T	p.Arg244Trp	missense splice_region	Exon 7 of 18	NP_001341913.1	P22455-1
FGFR4	NM_002011.5		c.730C>T	p.Arg244Trp	missense splice_region	Exon 7 of 18	NP_002002.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGFR4	ENST00000292408.9	TSL:1 MANE Select	c.730C>T	p.Arg244Trp	missense splice_region	Exon 7 of 18	ENSP00000292408.4	P22455-1
FGFR4	ENST00000502906.5	TSL:1	c.730C>T	p.Arg244Trp	missense splice_region	Exon 7 of 18	ENSP00000424960.1	P22455-1
FGFR4	ENST00000393637.5	TSL:1	c.730C>T	p.Arg244Trp	missense splice_region	Exon 6 of 16	ENSP00000377254.1	P22455-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000135

AC:

AN:

221820

AF XY:

0.0000166

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000337

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000987

Gnomad OTH exome

AF:

0.000188

GnomAD4 exome

AF:

0.00000776

AC:

AN:

1417288

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

699366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32352

American (AMR)

AF:

0.0000253

AC:

AN:

39558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23618

East Asian (EAS)

AF:

0.00

AC:

AN:

38974

South Asian (SAS)

AF:

0.00

AC:

AN:

81674

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5180

European-Non Finnish (NFE)

AF:

0.00000829

AC:

AN:

1085584

Other (OTH)

AF:

0.00

AC:

AN:

58256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.8

PhyloP100

1.6

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.78

Gain of catalytic residue at L242 (P = 0.003)

MVP

0.95

MPC

0.97

ClinPred

1.0

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.71

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over