chr2-73264462-C-T

Variant names:

• chr2-73264462-C-T
• rs748513064
• NM_001371389.2:c.1622G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001371389.2(FBXO41):​c.1622G>A​(p.Arg541His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. R541C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: FBXO41 NM_001371389.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.50
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03638217).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371389.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO41	NM_001371389.2	MANE Select	c.1622G>A	p.Arg541His	missense	Exon 6 of 13	NP_001358318.1	Q8TF61
	FBXO41	NM_001080410.4		c.1622G>A	p.Arg541His	missense	Exon 10 of 17	NP_001073879.2	Q8TF61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO41	ENST00000520530.3	TSL:5 MANE Select	c.1622G>A	p.Arg541His	missense	Exon 6 of 13	ENSP00000430968.2	Q8TF61
	FBXO41	ENST00000295133.9	TSL:1	c.1622G>A	p.Arg541His	missense	Exon 5 of 12	ENSP00000295133.6	Q8TF61
	FBXO41	ENST00000521871.5	TSL:5	c.1622G>A	p.Arg541His	missense	Exon 6 of 13	ENSP00000428646.1	Q8TF61

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152210 Hom.: 0 Cov.: 33

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: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000238 AC: 59 AN: 247810 AF XY: 0.000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.000287

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000158 AC: 231 AN: 1461588 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 147 AN XY: 727082

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86258

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53288

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000137 AC: 152 AN: 1111862

Other (OTH) AF: 0.000133 AC: 8 AN: 60374

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000223 AC: 27

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.11	N
PhyloP100		3.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Benign	0.068	T
Sift4G	Benign	0.18	T
Polyphen		0.032	B
Vest4		0.19
MVP		0.23
MPC		1.1
ClinPred		0.082	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.27
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs748513064; hg19: chr2-73491590;