1-10106370-C-A

Variant names:

• chr1-10106370-C-A
• rs755292165
• NM_001105562.3:c.983C>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001105562.3(UBE4B):​c.983C>A​(p.Pro328Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P328L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: UBE4B NM_001105562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046153188).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE4B	NM_001105562.3	c.983C>A	p.Pro328Gln	missense_variant	Exon 7 of 28	ENST00000343090.11	NP_001099032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE4B	ENST00000343090.11	c.983C>A	p.Pro328Gln	missense_variant	Exon 7 of 28	1	NM_001105562.3	ENSP00000343001.6
UBE4B	ENST00000253251.12	c.809+626C>A		intron_variant	Intron 6 of 26	1		ENSP00000253251.8
UBE4B	ENST00000672724.1	c.983C>A	p.Pro328Gln	missense_variant	Exon 7 of 29			ENSP00000500453.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249312 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461540 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 726980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.024
Sift	Benign	0.77	T
Sift4G	Benign	0.33	T
Polyphen		0.0030	B
Vest4		0.16
MutPred		0.33		Loss of glycosylation at P328 (P = 0.0065);
MVP		0.20
MPC		0.88
ClinPred		0.22	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.038
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs755292165; hg19: chr1-10166428;