Genetic Variant UBE4A:p.Ala184Val (chr11-118371656-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001204077.2(UBE4A):c.551C>T(p.Ala184Val) 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UBE4A
NM_001204077.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.49

Publications

0 publications found

Variant links:

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]

UBE4A Gene-Disease associations (from GenCC):

neurodevelopmental disorder with hypotonia and gross motor and speech delay
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
multiple congenital anomalies/dysmorphic syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

UBE4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204077.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE4A	NM_001204077.2	MANE Select	c.551C>T	p.Ala184Val	missense	Exon 5 of 20	NP_001191006.1	Q14139-1
	UBE4A	NM_004788.4		c.551C>T	p.Ala184Val	missense	Exon 5 of 20	NP_004779.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UBE4A	ENST00000252108.8	TSL:1 MANE Select	c.551C>T	p.Ala184Val	missense	Exon 5 of 20	ENSP00000252108.4	Q14139-1
UBE4A	ENST00000431736.6	TSL:1	c.551C>T	p.Ala184Val	missense	Exon 5 of 20	ENSP00000387362.2	Q14139-2
UBE4A	ENST00000911347.1		c.551C>T	p.Ala184Val	missense	Exon 5 of 20	ENSP00000581406.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726278

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111800

Other (OTH)

AF:

0.00

AC:

AN:

60360

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

7.5

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.42

REVEL

Benign

0.27

Sift

Benign

0.19

Sift4G

Benign

0.24

Polyphen

0.79

Vest4

0.79

MutPred

0.35

Gain of methylation at K185 (P = 0.0414)

MVP

0.15

MPC

0.38

ClinPred

0.89

GERP RS

5.6

Varity_R

0.18

gMVP

0.52

Mutation Taster

=51/49

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over