11-118369488-G-A

Position:

• chr11-118369488-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001204077.2(UBE4A):​c.361G>A​(p.Val121Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UBE4A NM_001204077.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

Genes affected

UBE4A (HGNC:12499): (ubiquitination factor E4A) This gene encodes a member of the U-box ubiquitin ligase family. The encoded protein is involved in multiubiquitin chain assembly and plays a critical role in chromosome condensation and separation through the polyubiquitination of securin. Autoantibodies against the encoded protein may be markers for scleroderma and Crohn's disease. A pseudogene of this gene is located on the long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.075371206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE4A	NM_001204077.2	c.361G>A	p.Val121Ile	missense_variant	4/20	ENST00000252108.8	NP_001191006.1
UBE4A	NM_004788.4	c.361G>A	p.Val121Ile	missense_variant	4/20		NP_004779.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE4A	ENST00000252108.8	c.361G>A	p.Val121Ile	missense_variant	4/20	1	NM_001204077.2	ENSP00000252108.4
UBE4A	ENST00000431736.6	c.361G>A	p.Val121Ile	missense_variant	4/20	1		ENSP00000387362.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727236

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2024

The c.361G>A (p.V121I) alteration is located in exon 4 (coding exon 3) of the UBE4A gene. This alteration results from a G to A substitution at nucleotide position 361, causing the valine (V) at amino acid position 121 to be replaced by an isoleucine (I). 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	0.079
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.044
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.077
Sift	Benign	0.28	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0	B;B
Vest4		0.13
MutPred		0.38		Loss of catalytic residue at V121 (P = 0.0444);Loss of catalytic residue at V121 (P = 0.0444);
MVP		0.12
MPC		0.25
ClinPred		0.59	D
GERP RS		5.0
Varity_R		0.027
gMVP		0.11

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: rs1948591218; hg19: chr11-118240203;