NM_001105562.3:c.578A>G

Variant names:

• chr1-10103090-A-G
• rs146544433
• NM_001105562.3:c.578A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. 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
• Publications: 5 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03860143).
• BS2: High AC in GnomAd4 at 121 AD gene.

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.578A>G	p.Glu193Gly	missense splice_region	Exon 5 of 28	NP_001099032.1	O95155-1
	UBE4B	NM_001410744.1		c.578A>G	p.Glu193Gly	missense splice_region	Exon 5 of 29	NP_001397673.1	O95155-4
	UBE4B	NM_006048.5		c.578A>G	p.Glu193Gly	missense splice_region	Exon 5 of 27	NP_006039.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE4B	ENST00000343090.11	TSL:1 MANE Select	c.578A>G	p.Glu193Gly	missense splice_region	Exon 5 of 28	ENSP00000343001.6	O95155-1
	UBE4B	ENST00000253251.12	TSL:1	c.578A>G	p.Glu193Gly	missense splice_region	Exon 5 of 27	ENSP00000253251.8	O95155-2
	UBE4B	ENST00000672724.1		c.578A>G	p.Glu193Gly	missense splice_region	Exon 5 of 29	ENSP00000500453.1	O95155-4

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

GnomAD2 exomes AF: 0.000757 AC: 188 AN: 248322 AF XY: 0.000781

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 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

African (AFR) AF: 0.000180 AC: 6 AN: 33310

American (AMR) AF: 0.000203 AC: 9 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.000347 AC: 9 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.000455 AC: 39 AN: 85764

European-Finnish (FIN) AF: 0.000471 AC: 24 AN: 50970

Middle Eastern (MID) AF: 0.00122 AC: 6 AN: 4934

European-Non Finnish (NFE) AF: 0.00124 AC: 1371 AN: 1105520

Other (OTH) AF: 0.000668 AC: 40 AN: 59866

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

African (AFR) AF: 0.000241 AC: 10 AN: 41426

American (AMR) AF: 0.000131 AC: 2 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68012

Other (OTH) AF: 0.00191 AC: 4 AN: 2090

Alfa AF: 0.00119 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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.077
Sift	Benign	0.22	T
Sift4G	Benign	0.24	T
Polyphen		0.0040	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
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs146544433; hg19: chr1-10163148;