NM_001105562.3:c.348-3A>C

Variant names:

• chr1-10101105-A-C
• rs78519671
• NM_001105562.3:c.348-3A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001105562.3(UBE4B):​c.348-3A>C variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.001032
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.02
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -18 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 VariationId is 775508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105562.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE4B	NM_001105562.3	MANE Select	c.348-3A>C		splice_region intron	N/A	NP_001099032.1	O95155-1
	UBE4B	NM_001410744.1		c.348-3A>C		splice_region intron	N/A	NP_001397673.1	O95155-4
	UBE4B	NM_006048.5		c.348-3A>C		splice_region intron	N/A	NP_006039.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE4B	ENST00000343090.11	TSL:1 MANE Select	c.348-3A>C		splice_region intron	N/A	ENSP00000343001.6	O95155-1
	UBE4B	ENST00000253251.12	TSL:1	c.348-3A>C		splice_region intron	N/A	ENSP00000253251.8	O95155-2
	UBE4B	ENST00000672724.1		c.348-3A>C		splice_region intron	N/A	ENSP00000500453.1	O95155-4

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

GnomAD2 exomes AF: 0.00486 AC: 1221 AN: 251422 AF XY: 0.00395

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 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

African (AFR) AF: 0.0602 AC: 2015 AN: 33468

American (AMR) AF: 0.00474 AC: 212 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5768

European-Non Finnish (NFE) AF: 0.000681 AC: 757 AN: 1111778

Other (OTH) AF: 0.00437 AC: 264 AN: 60380

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

African (AFR) AF: 0.0552 AC: 2296 AN: 41586

American (AMR) AF: 0.00601 AC: 92 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68036

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00858 Hom.: 25

Bravo AF: 0.0183

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.94
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs78519671; hg19: chr1-10161163;