chr1-10072142-C-T

Variant names:

• chr1-10072142-C-T
• rs1288333151
• NM_001105562.3:c.139C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001105562.3(UBE4B):​c.139C>T​(p.Pro47Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UBE4B NM_001105562.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32254988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE4B	NM_001105562.3	c.139C>T	p.Pro47Ser	missense_variant	Exon 2 of 28	ENST00000343090.11	NP_001099032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE4B	ENST00000343090.11	c.139C>T	p.Pro47Ser	missense_variant	Exon 2 of 28	1	NM_001105562.3	ENSP00000343001.6
UBE4B	ENST00000253251.12	c.139C>T	p.Pro47Ser	missense_variant	Exon 2 of 27	1		ENSP00000253251.8
UBE4B	ENST00000672724.1	c.139C>T	p.Pro47Ser	missense_variant	Exon 2 of 29			ENSP00000500453.1
UBE4B	ENST00000377153.5	c.139C>T	p.Pro47Ser	missense_variant	Exon 2 of 3	3		ENSP00000366358.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461572 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727094

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139C>T (p.P47S) alteration is located in exon 2 (coding exon 2) of the UBE4B gene. This alteration results from a C to T substitution at nucleotide position 139, causing the proline (P) at amino acid position 47 to be replaced by a serine (S). 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	0.072
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	.;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;D;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.6	L;.;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.4	N;D;N
REVEL	Benign	0.25
Sift	Benign	0.066	T;D;D
Sift4G	Benign	0.13	T;D;D
Polyphen		1.0	D;.;D
Vest4		0.47
MutPred		0.22		Gain of phosphorylation at P47 (P = 0.0191);Gain of phosphorylation at P47 (P = 0.0191);Gain of phosphorylation at P47 (P = 0.0191);
MVP		0.54
MPC		0.72
ClinPred		0.95	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1288333151; hg19: chr1-10132200; COSMIC: COSV104583126;