1-10101105-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001105562.3(UBE4B):c.348-3A>C variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0036 in 1,613,930 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (59 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (64 hom.)
• Consequence: UBE4B NM_001105562.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001032
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.02

Genes affected

UBE4B (HGNC:12500): (ubiquitination factor E4B) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes an additional conjugation factor, E4, which is involved in multiubiquitin chain assembly. This gene is also the strongest candidate in the neuroblastoma tumor suppressor genes. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 1-10101105-A-C is Benign according to our data. Variant chr1-10101105-A-C is described in ClinVar as [Benign]. Clinvar id is 775508.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE4B	NM_001105562.3	c.348-3A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000343090.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE4B	ENST00000343090.11	c.348-3A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001105562.3
UBE4B	ENST00000253251.12	c.348-3A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
UBE4B	ENST00000672724.1	c.348-3A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
UBE4B	ENST00000462658.1	n.245A>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2471 AN: 152232 Hom.: 59 Cov.: 33

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00486 AC: 1221 AN: 251422 Hom.: 21 AF XY: 0.00395 AC XY: 537 AN XY: 135904

Gnomad AFR exome AF: 0.0589

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000897

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00228 AC: 3330 AN: 1461580 Hom.: 64 Cov.: 30 AF XY: 0.00205 AC XY: 1490 AN XY: 727118

Gnomad4 AFR exome AF: 0.0602

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000681

Gnomad4 OTH exome AF: 0.00437

GnomAD4 genome AF: 0.0162 AC: 2473 AN: 152350 Hom.: 59 Cov.: 33 AF XY: 0.0161 AC XY: 1196 AN XY: 74504

Gnomad4 AFR AF: 0.0552

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00828 Hom.: 19

Bravo AF: 0.0183

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	14
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.16
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: rs78519671; hg19: chr1-10161163;