chr2-73263977-C-T

Variant names:

• chr2-73263977-C-T
• rs778503960
• NM_001371389.2:c.1883G>A

Variant summary

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

The NM_001371389.2(FBXO41):​c.1883G>A​(p.Gly628Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,454,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G628V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: FBXO41 NM_001371389.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.69

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, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO41	NM_001371389.2	c.1883G>A	p.Gly628Glu	missense_variant	Exon 7 of 13	ENST00000520530.3	NP_001358318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO41	ENST00000520530.3	c.1883G>A	p.Gly628Glu	missense_variant	Exon 7 of 13	5	NM_001371389.2	ENSP00000430968.2
FBXO41	ENST00000295133.9	c.1883G>A	p.Gly628Glu	missense_variant	Exon 6 of 12	1		ENSP00000295133.6
FBXO41	ENST00000521871.5	c.1883G>A	p.Gly628Glu	missense_variant	Exon 7 of 13	5		ENSP00000428646.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000428 AC: 1 AN: 233916 Hom.: 0 AF XY: 0.00000787 AC XY: 1 AN XY: 127002

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000951

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000268 AC: 39 AN: 1454506 Hom.: 0 Cov.: 33 AF XY: 0.0000249 AC XY: 18 AN XY: 722888

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000343

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;.;.
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.7	.;D;.
REVEL	Uncertain	0.31
Sift	Benign	0.064	.;T;.
Sift4G	Uncertain	0.037	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.36		Loss of MoRF binding (P = 0.0179);Loss of MoRF binding (P = 0.0179);Loss of MoRF binding (P = 0.0179);
MVP		0.35
MPC		1.2
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.53
gMVP		0.69

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: rs778503960; hg19: chr2-73491105;