Genetic Variant NM_207102.2:c.191C>T (chr3-48373610-C-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_207102.2(FBXW12):c.191C>T(p.Thr64Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 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. T64K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FBXW12
NM_207102.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.140

Publications

0 publications found

Variant links:

Genes affected

FBXW12 (HGNC:20729): (F-box and WD repeat domain containing 12) Members of the F-box protein family, such as FBXW12, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603034), 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]

FBXW12 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;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207102.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXW12	NM_207102.2	MANE Select	c.191C>T	p.Thr64Ile	missense	Exon 4 of 11	NP_996985.2	Q6X9E4-1
FBXW12	NM_001159929.1		c.134C>T	p.Thr45Ile	missense	Exon 3 of 10	NP_001153401.1	Q6X9E4-3
FBXW12	NM_001159927.1		c.191C>T	p.Thr64Ile	missense	Exon 4 of 10	NP_001153399.1	Q6X9E4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBXW12	ENST00000296438.9	TSL:1 MANE Select	c.191C>T	p.Thr64Ile	missense	Exon 4 of 11	ENSP00000296438.5	Q6X9E4-1
FBXW12	ENST00000445170.5	TSL:1	c.134C>T	p.Thr45Ile	missense	Exon 3 of 10	ENSP00000406139.1	Q6X9E4-3
FBXW12	ENST00000415155.5	TSL:1	c.191C>T	p.Thr64Ile	missense	Exon 4 of 10	ENSP00000414683.1	Q6X9E4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251450

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

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:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.49

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PhyloP100

0.14

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.7

REVEL

Benign

0.041

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.024

Polyphen

0.99

Vest4

0.38

MutPred

0.45

Gain of helix (P = 0.0128)

MVP

0.39

MPC

0.43

ClinPred

0.83

GERP RS

2.8

Varity_R

0.36

gMVP

0.40

Mutation Taster

=90/10

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over