2-230010736-C-G

Variant names:

• chr2-230010736-C-G
• rs763837354
• NM_174899.5:c.419C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174899.5(FBXO36):​c.419C>G​(p.Ser140Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. S140L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBXO36 NM_174899.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0430
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19746602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO36	NM_174899.5	c.419C>G	p.Ser140Trp	missense_variant	Exon 4 of 4	ENST00000283946.8	NP_777559.3
FBXO36	XM_005246317.3	c.344C>G	p.Ser115Trp	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.419C>G	p.Ser140Trp	missense_variant	Exon 4 of 4	1	NM_174899.5	ENSP00000283946.3
FBXO36	ENST00000373652.7	c.326C>G	p.Ser109Trp	missense_variant	Exon 5 of 5	1		ENSP00000362756.3
FBXO36	ENST00000409992.1	c.359C>G	p.Ser120Trp	missense_variant	Exon 4 of 4	5		ENSP00000386673.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250668 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461276 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000448 AC: 2 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111572

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.000196 AC: 3 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	.;M;.
PhyloP100		-0.043
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.089
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.98	.;D;.
Vest4		0.41
MutPred		0.32		.;Gain of helix (P = 0.0696);.;
MVP		0.37
MPC		0.30
ClinPred		0.72	D
GERP RS		-1.1
Varity_R		0.12
gMVP		0.26
Mutation Taster		=84/16	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: rs763837354; hg19: chr2-230875452;