14-55351211-G-A

Position:

• chr14-55351211-G-A

Variant summary

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

The ENST00000313833.5(FBXO34):​c.821G>A​(p.Ser274Asn) 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. 14/21 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: FBXO34 ENST00000313833.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.850

Genes affected

FBXO34 (HGNC:20201): (F-box protein 34) Members of the F-box protein family, such as FBXO34, 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

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=0.039168507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXO34	NM_017943.4	c.821G>A	p.Ser274Asn	missense_variant	2/2	ENST00000313833.5	NP_060413.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXO34	ENST00000313833.5	c.821G>A	p.Ser274Asn	missense_variant	2/2	1	NM_017943.4	ENSP00000313159	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2022

The c.821G>A (p.S274N) alteration is located in exon 2 (coding exon 1) of the FBXO34 gene. This alteration results from a G to A substitution at nucleotide position 821, causing the serine (S) at amino acid position 274 to be replaced by an asparagine (N). 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	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.78
DEOGEN2	Benign	0.0063	T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.57	.;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.030
Sift	Benign	0.47	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0070	B;B
Vest4		0.086
MutPred		0.18		Loss of phosphorylation at S274 (P = 0.0462);Loss of phosphorylation at S274 (P = 0.0462);
MVP		0.27
MPC		0.12
ClinPred		0.083	T
GERP RS		3.6
Varity_R		0.038
gMVP		0.11

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: rs1359668403; hg19: chr14-55817929;