Genetic Variant UBE4B:p.Pro37Leu (chr1-10072113-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BS2

The NM_001105562.3(UBE4B):c.110C>T(p.Pro37Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

UBE4B
NM_001105562.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.31

Variant links:

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]

UBE4B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE4B	NM_001105562.3 link	c.110C>T	p.Pro37Leu	missense_variant	Exon 2 of 28	ENST00000343090.11	NP_001099032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBE4B	ENST00000343090.11 link	c.110C>T	p.Pro37Leu	missense_variant	Exon 2 of 28	1	NM_001105562.3	ENSP00000343001.6	O95155-1
UBE4B	ENST00000253251.12 link	c.110C>T	p.Pro37Leu	missense_variant	Exon 2 of 27	1		ENSP00000253251.8	O95155-2
UBE4B	ENST00000672724.1 link	c.110C>T	p.Pro37Leu	missense_variant	Exon 2 of 29			ENSP00000500453.1	O95155-4
UBE4B	ENST00000377153.5 link	c.110C>T	p.Pro37Leu	missense_variant	Exon 2 of 3	3		ENSP00000366358.1	B1AQ61

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250782

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135586

show subpopulations

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:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461444

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.110C>T (p.P37L) 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 110, causing the proline (P) at amino acid position 37 to be replaced by a leucine (L). 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

0.14

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

.;T;T

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.7

L;.;L

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.5

D;D;N

REVEL

Uncertain

0.38

Sift

Benign

0.040

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.60

MutPred

0.26

Loss of glycosylation at P37 (P = 0.0429);Loss of glycosylation at P37 (P = 0.0429);Loss of glycosylation at P37 (P = 0.0429);

MVP

0.41

MPC

0.78

ClinPred

0.92

GERP RS

4.5

Varity_R

0.26

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over