2-230010868-G-A

Variant names:

• chr2-230010868-G-A
• rs368835857
• NM_174899.5:c.551G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_174899.5(FBXO36):​c.551G>A​(p.Arg184Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBXO36 NM_174899.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.10
• Publications: 0 publications found

Genes affected

FBXO36 (HGNC:27020): (F-box protein 36) Members of the F-box protein family, such as FBXO36, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0421941).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO36	NM_174899.5	c.551G>A	p.Arg184Lys	missense_variant	Exon 4 of 4	ENST00000283946.8	NP_777559.3
FBXO36	XM_005246317.3	c.476G>A	p.Arg159Lys	missense_variant	Exon 4 of 4		XP_005246374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO36	ENST00000283946.8	c.551G>A	p.Arg184Lys	missense_variant	Exon 4 of 4	1	NM_174899.5	ENSP00000283946.3
FBXO36	ENST00000373652.7	c.458G>A	p.Arg153Lys	missense_variant	Exon 5 of 5	1		ENSP00000362756.3
FBXO36	ENST00000409992.1	c.491G>A	p.Arg164Lys	missense_variant	Exon 4 of 4	5		ENSP00000386673.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.551G>A (p.R184K) alteration is located in exon 4 (coding exon 4) of the FBXO36 gene. This alteration results from a G to A substitution at nucleotide position 551, causing the arginine (R) at amino acid position 184 to be replaced by a lysine (K). 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	0.073
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.020
DANN	Benign	0.42
DEOGEN2	Benign	0.00058	.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.43	T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;.
PhyloP100		-1.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.030	N;N;N
REVEL	Benign	0.0020
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.051
MutPred		0.19		.;Gain of methylation at R184 (P = 0.0149);.;
MVP		0.19
MPC		0.049
ClinPred		0.041	T
GERP RS		-4.3
Varity_R		0.036
gMVP		0.15
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs368835857; hg19: chr2-230875584;