1-10103090-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001105562.3(UBE4B):c.578A>G(p.Glu193Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00101 in 1,602,338 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: UBE4B NM_001105562.3 missense, splice_region
• Scores: Splicing: ADA: 0.005145
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.05

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, UBE4B
• BP4: Computational evidence support a benign effect (MetaRNN=0.03860143).
• BS2: High AC in GnomAd at 121 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE4B	NM_001105562.3	c.578A>G	p.Glu193Gly	missense_variant, splice_region_variant	5/28	ENST00000343090.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE4B	ENST00000343090.11	c.578A>G	p.Glu193Gly	missense_variant, splice_region_variant	5/28	1	NM_001105562.3
UBE4B	ENST00000253251.12	c.578A>G	p.Glu193Gly	missense_variant, splice_region_variant	5/27	1		P1
UBE4B	ENST00000672724.1	c.578A>G	p.Glu193Gly	missense_variant, splice_region_variant	5/29
UBE4B	ENST00000462658.1	n.478A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152120 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000757 AC: 188 AN: 248322 Hom.: 1 AF XY: 0.000781 AC XY: 105 AN XY: 134412

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.000400

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000459

Gnomad FIN exome AF: 0.000400

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.00104 AC: 1504 AN: 1450218 Hom.: 2 Cov.: 30 AF XY: 0.00104 AC XY: 747 AN XY: 720530

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.000347

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000455

Gnomad4 FIN exome AF: 0.000471

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.000668

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152120 Hom.: 0 Cov.: 30 AF XY: 0.000713 AC XY: 53 AN XY: 74304

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.000839

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000824 AC: 100

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

Aug 16, 2021

The c.578A>G (p.E193G) alteration is located in exon 5 (coding exon 5) of the UBE4B gene. This alteration results from a A to G substitution at nucleotide position 578, causing the glutamic acid (E) at amino acid position 193 to be replaced by a glycine (G). 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	-0.39	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Benign	-0.11
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Benign	0.077
Sift	Benign	0.22	T;D
Sift4G	Benign	0.24	T;T
Polyphen		0.0040	B;B
Vest4		0.46
MVP		0.15
MPC		0.35
ClinPred		0.044	T
GERP RS		4.8
Varity_R		0.10
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0051
dbscSNV1_RF	Benign	0.086
SpliceAI score (max)		0.010		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: rs146544433; hg19: chr1-10163148;