11-118373103-G-C

Position:

• chr11-118373103-G-C

Variant summary

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

The NM_001204077.2(UBE4A):​c.739G>C​(p.Glu247Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE4A NM_001204077.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE4A	NM_001204077.2	c.739G>C	p.Glu247Gln	missense_variant	7/20	ENST00000252108.8	NP_001191006.1
UBE4A	NM_004788.4	c.760G>C	p.Glu254Gln	missense_variant	7/20		NP_004779.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE4A	ENST00000252108.8	c.739G>C	p.Glu247Gln	missense_variant	7/20	1	NM_001204077.2	ENSP00000252108	P1
UBE4A	ENST00000431736.6	c.760G>C	p.Glu254Gln	missense_variant	7/20	1		ENSP00000387362

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 12, 2022

The c.760G>C (p.E254Q) alteration is located in exon 7 (coding exon 6) of the UBE4A gene. This alteration results from a G to C substitution at nucleotide position 760, causing the glutamic acid (E) at amino acid position 254 to be replaced by a glutamine (Q). 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	0.12
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.43	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.19	T;T
Sift4G	Benign	0.51	T;T
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.34		Gain of helix (P = 0.2059);.;
MVP		0.26
MPC		0.65
ClinPred		0.85	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.33

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: rs1225376416; hg19: chr11-118243818;