3-33402834-G-A

Position:

• chr3-33402834-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014517.5(UBP1):​c.998C>T​(p.Ser333Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S333P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBP1 NM_014517.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

UBP1 (HGNC:12507): (upstream binding protein 1) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in negative regulation of viral transcription and positive regulation of transcription by RNA polymerase II. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

FBXL2 (HGNC:13598): (F-box and leucine rich repeat protein 2) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains 12 tandem leucine-rich repeats. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UBP1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBP1	NM_014517.5	c.998C>T	p.Ser333Phe	missense_variant	9/16	ENST00000283629.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBP1	ENST00000283629.8	c.998C>T	p.Ser333Phe	missense_variant	9/16	1	NM_014517.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jan 29, 2024

The c.998C>T (p.S333F) alteration is located in exon 9 (coding exon 9) of the UBP1 gene. This alteration results from a C to T substitution at nucleotide position 998, causing the serine (S) at amino acid position 333 to be replaced by a phenylalanine (F). 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	0.11
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.029	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.55	P;P;P
Vest4		0.58
MutPred		0.30		Loss of glycosylation at P329 (P = 0.0167);.;Loss of glycosylation at P329 (P = 0.0167);
MVP		0.17
MPC		0.38
ClinPred		0.96	D
GERP RS		6.2
Varity_R		0.29
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-33444326;