Genetic Variant UBE4A:c.-167A>T (chr11-118359549-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001204077.2(UBE4A):c.-167A>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,110 control chromosomes in the GnomAD database, including 2,962 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.18 ( 2962 hom., cov: 32)

Exomes 𝑓: 0.10 ( 0 hom. )

Consequence

UBE4A
NM_001204077.2 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.397

Publications

11 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE4A	NM_001204077.2 link	c.-167A>T		upstream_gene_variant		ENST00000252108.8	NP_001191006.1
UBE4A	NM_004788.4 link	c.-167A>T		upstream_gene_variant			NP_004779.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE4A	ENST00000252108.8 link	c.-167A>T		upstream_gene_variant		1	NM_001204077.2	ENSP00000252108.4		Q14139-1
UBE4A	ENST00000431736.6 link	c.-167A>T		upstream_gene_variant		1		ENSP00000387362.2		Q14139-2

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27134

AN:

151942

Hom.:

2969

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.232

Gnomad EAS

AF:

0.507

Gnomad SAS

AF:

0.467

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.170

GnomAD4 exome

AF:

0.100

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0833

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.105

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.179

AC:

27151

AN:

152060

Hom.:

2962

Cov.:

AF XY:

0.187

AC XY:

13892

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.159

AC:

6596

AN:

41488

American (AMR)

AF:

0.123

AC:

1877

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

807

AN:

3472

East Asian (EAS)

AF:

0.507

AC:

2615

AN:

5158

South Asian (SAS)

AF:

0.465

AC:

2240

AN:

4816

European-Finnish (FIN)

AF:

0.189

AC:

1989

AN:

10550

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.154

AC:

10483

AN:

67986

Other (OTH)

AF:

0.173

AC:

366

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1081

2161

3242

4322

5403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

318

636

954

1272

1590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0765

Hom.:

Bravo

AF:

0.168

Asia WGS

AF:

0.449

AC:

1559

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.8

(source)

DANN

Benign

0.82

PhyloP100

-0.40

PromoterAI

-0.15

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over