3-33402794-T-G

Variant names:

• chr3-33402794-T-G
• rs623244
• NM_014517.5:c.1031+7A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014517.5(UBP1):​c.1031+7A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 1,545,238 control chromosomes in the GnomAD database, including 363,820 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (29895 hom., cov: 31)
  • Exomes 𝑓: 0.69 (333925 hom.)
• Consequence: UBP1 NM_014517.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002643
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0800
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBP1	NM_014517.5	c.1031+7A>C		splice_region_variant, intron_variant	Intron 9 of 15	ENST00000283629.8	NP_055332.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBP1	ENST00000283629.8	c.1031+7A>C		splice_region_variant, intron_variant	Intron 9 of 15	1	NM_014517.5	ENSP00000283629.3

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93611 AN: 151724 Hom.: 29881 Cov.: 31

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.605

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.626

GnomAD2 exomes AF: 0.618 AC: 114080 AN: 184548 AF XY: 0.633

Gnomad AFR exome AF: 0.497

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.376

Gnomad FIN exome AF: 0.651

Gnomad NFE exome AF: 0.720

Gnomad OTH exome AF: 0.644

GnomAD4 exome AF: 0.687 AC: 957650 AN: 1393396 Hom.: 333925 Cov.: 28 AF XY: 0.687 AC XY: 473271 AN XY: 688702

African (AFR) AF: 0.497 AC: 15115 AN: 30408

American (AMR) AF: 0.371 AC: 11472 AN: 30948

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 16182 AN: 22688

East Asian (EAS) AF: 0.459 AC: 17362 AN: 37828

South Asian (SAS) AF: 0.632 AC: 48225 AN: 76286

European-Finnish (FIN) AF: 0.658 AC: 33598 AN: 51046

Middle Eastern (MID) AF: 0.711 AC: 3903 AN: 5488

European-Non Finnish (NFE) AF: 0.715 AC: 773632 AN: 1081270

Other (OTH) AF: 0.664 AC: 38161 AN: 57434

GnomAD4 genome AF: 0.617 AC: 93650 AN: 151842 Hom.: 29895 Cov.: 31 AF XY: 0.610 AC XY: 45266 AN XY: 74216

African (AFR) AF: 0.509 AC: 21057 AN: 41356

American (AMR) AF: 0.485 AC: 7403 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2485 AN: 3470

East Asian (EAS) AF: 0.402 AC: 2071 AN: 5150

South Asian (SAS) AF: 0.619 AC: 2978 AN: 4814

European-Finnish (FIN) AF: 0.646 AC: 6795 AN: 10514

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.715 AC: 48610 AN: 67974

Other (OTH) AF: 0.619 AC: 1304 AN: 2106

Alfa AF: 0.683 Hom.: 46710

Bravo AF: 0.594

Asia WGS AF: 0.472 AC: 1642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.6
DANN	Benign	0.63
PhyloP100		-0.080
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.028
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: rs623244; hg19: chr3-33444286; COSMIC: COSV52145541; COSMIC: COSV52145541;