2-73258990-C-T

Variant names:

• chr2-73258990-C-T
• rs199625082
• NM_001371389.2:c.2620G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001371389.2(FBXO41):​c.2620G>A​(p.Gly874Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,581,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: FBXO41 NM_001371389.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0439063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO41	NM_001371389.2	c.2620G>A	p.Gly874Ser	missense_variant	Exon 13 of 13	ENST00000520530.3	NP_001358318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO41	ENST00000520530.3	c.2620G>A	p.Gly874Ser	missense_variant	Exon 13 of 13	5	NM_001371389.2	ENSP00000430968.2
FBXO41	ENST00000295133.9	c.2620G>A	p.Gly874Ser	missense_variant	Exon 12 of 12	1		ENSP00000295133.6
FBXO41	ENST00000521871.5	c.2620G>A	p.Gly874Ser	missense_variant	Exon 13 of 13	5		ENSP00000428646.1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000133 AC: 26 AN: 196122 Hom.: 0 AF XY: 0.000132 AC XY: 14 AN XY: 106280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000790

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000215

Gnomad OTH exome AF: 0.000200

GnomAD4 exome AF: 0.000162 AC: 232 AN: 1429334 Hom.: 0 Cov.: 31 AF XY: 0.000154 AC XY: 109 AN XY: 708150

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.000173

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000858

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.0000508

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74362

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000252 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.000266 AC: 1

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2620G>A (p.G874S) alteration is located in exon 12 (coding exon 12) of the FBXO41 gene. This alteration results from a G to A substitution at nucleotide position 2620, causing the glycine (G) at amino acid position 874 to be replaced by a serine (S). 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	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.83	T;.;.
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.070	.;N;.
REVEL	Benign	0.060
Sift	Benign	0.26	.;T;.
Sift4G	Benign	0.57	T;T;T
Polyphen		0.58	P;P;P
Vest4		0.061
MVP		0.20
MPC		0.84
ClinPred		0.10	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.19

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: rs199625082; hg19: chr2-73486118;