2-230010735-T-C

Variant names:

• chr2-230010735-T-C
• NM_174899.5:c.418T>C

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.418T>C​(p.Ser140Pro) 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. 13/22 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. S140L) has been classified 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: 0.361
• 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: 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=0.14522159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO36	NM_174899.5	c.418T>C	p.Ser140Pro	missense_variant	Exon 4 of 4	ENST00000283946.8	NP_777559.3
FBXO36	XM_005246317.3	c.343T>C	p.Ser115Pro	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.418T>C	p.Ser140Pro	missense_variant	Exon 4 of 4	1	NM_174899.5	ENSP00000283946.3
FBXO36	ENST00000373652.7	c.325T>C	p.Ser109Pro	missense_variant	Exon 5 of 5	1		ENSP00000362756.3
FBXO36	ENST00000409992.1	c.358T>C	p.Ser120Pro	missense_variant	Exon 4 of 4	5		ENSP00000386673.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418T>C (p.S140P) alteration is located in exon 4 (coding exon 4) of the FBXO36 gene. This alteration results from a T to C substitution at nucleotide position 418, causing the serine (S) at amino acid position 140 to be replaced by a proline (P). 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	Uncertain	0.47
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	.;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.39	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	.;M;.
PhyloP100		0.36
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.70	.;P;.
Vest4		0.38
MutPred		0.29		.;Loss of helix (P = 0.079);.;
MVP		0.33
MPC		0.16
ClinPred		0.19	T
GERP RS		0.85
Varity_R		0.43
gMVP		0.53
Mutation Taster		=80/20	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

hg19: chr2-230875451;