2-73264429-T-C

Position:

• chr2-73264429-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001371389.2(FBXO41):​c.1655A>G​(p.Lys552Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBXO41 NM_001371389.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

Genes affected

FBXO41 (HGNC:29409): (F-box protein 41) This gene encodes a member of the F-box protein family, which is characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one of the four subunits of the SCF ubiquitin protein ligase complex that plays a role in phosphorylation-dependent ubiquitination. F-box proteins are divided into three classes depending on the interaction substrate domain each contains in addition to the F-box motif: FBXW proteins contain WD-40 domains, FBXL proteins contain leucine-rich repeats, and FBXO proteins contain either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the FBXO class. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO41	NM_001371389.2	c.1655A>G	p.Lys552Arg	missense_variant	6/13	ENST00000520530.3	NP_001358318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO41	ENST00000520530.3	c.1655A>G	p.Lys552Arg	missense_variant	6/13	5	NM_001371389.2	ENSP00000430968.2
FBXO41	ENST00000295133.9	c.1655A>G	p.Lys552Arg	missense_variant	5/12	1		ENSP00000295133.6
FBXO41	ENST00000521871.5	c.1655A>G	p.Lys552Arg	missense_variant	6/13	5		ENSP00000428646.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.1655A>G (p.K552R) alteration is located in exon 5 (coding exon 5) of the FBXO41 gene. This alteration results from a A to G substitution at nucleotide position 1655, causing the lysine (K) at amino acid position 552 to be replaced by an arginine (R). 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	Benign	0.23
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;.
M_CAP	Benign	0.0077	T
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.92	.;N;.
REVEL	Benign	0.15
Sift	Benign	0.29	.;T;.
Sift4G	Benign	0.42	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.79
MutPred		0.47		Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);Gain of helix (P = 6e-04);
MVP		0.65
MPC		0.25
ClinPred		0.72	D
GERP RS		5.3
Varity_R		0.18
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-73491557;