14-39399635-C-A

Variant names:

• chr14-39399635-C-A
• rs1456450191
• NM_203301.4:c.1549G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_203301.4(FBXO33):​c.1549G>T​(p.Val517Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V517A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBXO33 NM_203301.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

Genes affected

FBXO33 (HGNC:19833): (F-box protein 33) This locus represents an member of the F-box gene family. The encoded protein contains an F-box motif and a domain that might form a structure similar to a leucine-rich repeat found in placental RNAse inhibitor. This locus may be associated with copy number variation of UGT2B17 (GeneID 7367), which has been associated with susceptibility to osteoporosis.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 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
FBXO33	NM_203301.4	c.1549G>T	p.Val517Leu	missense_variant	Exon 4 of 4	ENST00000298097.8	NP_976046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO33	ENST00000298097.8	c.1549G>T	p.Val517Leu	missense_variant	Exon 4 of 4	1	NM_203301.4	ENSP00000298097.7
FBXO33	ENST00000554190	c.*98G>T		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000451277.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1549G>T (p.V517L) alteration is located in exon 4 (coding exon 4) of the FBXO33 gene. This alteration results from a G to T substitution at nucleotide position 1549, causing the valine (V) at amino acid position 517 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.53		Gain of catalytic residue at L519 (P = 0.0012);
MVP		0.34
MPC		0.61
ClinPred		0.95	D
GERP RS		6.0
Varity_R		0.41
gMVP		0.84

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

Other links and lift over

dbSNP: rs1456450191; hg19: chr14-39868839;