2-229976337-T-G

Variant names:

• chr2-229976337-T-G
• NM_174899.5:c.193T>G

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.193T>G​(p.Ser65Ala) 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. 15/22 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: 0.218
• 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=0.06283948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO36	NM_174899.5	c.193T>G	p.Ser65Ala	missense_variant	Exon 2 of 4	ENST00000283946.8	NP_777559.3
FBXO36	XM_005246317.3	c.118T>G	p.Ser40Ala	missense_variant	Exon 2 of 4		XP_005246374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO36	ENST00000283946.8	c.193T>G	p.Ser65Ala	missense_variant	Exon 2 of 4	1	NM_174899.5	ENSP00000283946.3
FBXO36	ENST00000373652.7	c.100T>G	p.Ser34Ala	missense_variant	Exon 3 of 5	1		ENSP00000362756.3
FBXO36	ENST00000465090.2	n.216T>G		non_coding_transcript_exon_variant	Exon 2 of 2	1
FBXO36	ENST00000409992.1	c.193T>G	p.Ser65Ala	missense_variant	Exon 2 of 4	5		ENSP00000386673.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.193T>G (p.S65A) alteration is located in exon 2 (coding exon 2) of the FBXO36 gene. This alteration results from a T to G substitution at nucleotide position 193, causing the serine (S) at amino acid position 65 to be replaced by an alanine (A). 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	0.060
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.4
DANN	Benign	0.57
DEOGEN2	Benign	0.0033	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.16	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.063	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	.;M;.
PhyloP100		0.22
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.68	T;T;T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.0040, 0.0	.;B;B
Vest4		0.24
MutPred		0.21		.;Loss of stability (P = 0.034);Loss of stability (P = 0.034);
MVP		0.34
MPC		0.043
ClinPred		0.95	D
GERP RS		1.9
Varity_R		0.057
gMVP		0.13

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: chr2-230841053;