Genetic Variant FBXL20:p.Thr206Lys (chr17-39282733-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032875.3(FBXL20):c.617C>A(p.Thr206Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T206M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FBXL20
NM_032875.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.75

Publications

0 publications found

Variant links:

Genes affected

FBXL20 (HGNC:24679): (F-box and leucine rich repeat protein 20) Members of the F-box protein family, such as FBXL20, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

FBXL20 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL20	NM_032875.3 link	c.617C>A	p.Thr206Lys	missense_variant	Exon 8 of 15	ENST00000264658.11	NP_116264.2	Q96IG2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBXL20	ENST00000264658.11 link	c.617C>A	p.Thr206Lys	missense_variant	Exon 8 of 15	1	NM_032875.3	ENSP00000264658.6	Q96IG2-1
FBXL20	ENST00000394294.7 link	c.521C>A	p.Thr174Lys	missense_variant	Exon 7 of 14	1		ENSP00000377832.3	Q96IG2-2
FBXL20	ENST00000577399.5 link	c.623C>A	p.Thr208Lys	missense_variant	Exon 8 of 15	5		ENSP00000462878.1	J3KTA1
FBXL20	ENST00000583610.5 link	c.617C>A	p.Thr206Lys	missense_variant	Exon 8 of 16	2		ENSP00000462271.1	Q96IG2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727222

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001173), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.15

T;T;.;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

.;D;D;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.49

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;.;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.99

N;.;N;.

REVEL

Uncertain

0.34

Sift

Benign

0.96

T;.;T;.

Sift4G

Benign

0.92

T;T;T;T

Polyphen

0.043

B;B;D;.

Vest4

0.69

MutPred

0.54

Gain of methylation at T206 (P = 0.0062);Gain of methylation at T206 (P = 0.0062);.;.;

MVP

0.42

MPC

1.3

ClinPred

0.78

GERP RS

5.6

Varity_R

0.37

gMVP

0.77

Mutation Taster

=43/57

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over