Genetic Variant UBE4A:c.2412+22_2412+23dupAA (chr11-118384947-T-TAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001204077.2(UBE4A):c.2412+22_2412+23dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000885 in 1,066,192 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00088 ( 1 hom. )

Consequence

UBE4A
NM_001204077.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Publications

1 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:

LOC100131626 (HGNC:):

LOC100131626 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000994 (79/79466) while in subpopulation AFR AF = 0.00228 (50/21894). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
UBE4A	NM_001204077.2 link	c.2412+22_2412+23dupAA	intron_variant	Intron 15 of 19	ENST00000252108.8	NP_001191006.1
UBE4A	NM_004788.4 link	c.2433+22_2433+23dupAA	intron_variant	Intron 15 of 19		NP_004779.2
LOC100131626	NR_046369.1 link	n.232-3389_232-3388dupTT	intron_variant	Intron 3 of 3
LOC100131626	NR_046370.1 link	n.232-3442_232-3441dupTT	intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBE4A	ENST00000252108.8 link	c.2412+2_2412+3insAA	splice_region_variant, intron_variant	Intron 15 of 19	1	NM_001204077.2	ENSP00000252108.4	Q14139-1
UBE4A	ENST00000431736.6 link	c.2433+2_2433+3insAA	splice_region_variant, intron_variant	Intron 15 of 19	1		ENSP00000387362.2	Q14139-2
UBE4A	ENST00000545354.1 link	c.828+2_828+3insAA	splice_region_variant, intron_variant	Intron 6 of 10	2		ENSP00000438918.1	B7Z7P0

Frequencies

GnomAD3 genomes

AF:

0.000994

AC:

AN:

79476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00130

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000339

Gnomad SAS

AF:

0.00155

Gnomad FIN

AF:

0.000477

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000347

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000877

AC:

865

AN:

986726

Hom.:

Cov.:

AF XY:

0.000889

AC XY:

447

AN XY:

503060

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00130

AC:

AN:

22224

American (AMR)

AF:

0.000735

AC:

AN:

28560

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

18938

East Asian (EAS)

AF:

0.000575

AC:

AN:

34782

South Asian (SAS)

AF:

0.00151

AC:

AN:

63420

European-Finnish (FIN)

AF:

0.000464

AC:

AN:

34450

Middle Eastern (MID)

AF:

0.00103

AC:

AN:

3894

European-Non Finnish (NFE)

AF:

0.000845

AC:

623

AN:

737362

Other (OTH)

AF:

0.000812

AC:

AN:

43096

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.274

Heterozygous variant carriers

155

232

310

387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000994

AC:

AN:

79466

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

37768

show subpopulations

African (AFR)

AF:

0.00228

AC:

AN:

21894

American (AMR)

AF:

0.00130

AC:

AN:

6898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2000

East Asian (EAS)

AF:

0.000341

AC:

AN:

2934

South Asian (SAS)

AF:

0.00157

AC:

AN:

2548

European-Finnish (FIN)

AF:

0.000477

AC:

AN:

4190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

116

European-Non Finnish (NFE)

AF:

0.000348

AC:

AN:

37408

Other (OTH)

AF:

0.00

AC:

AN:

1028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=93/7

polymorphism

(source)

Splicing

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

Publications

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11-118384947-TAAAAAAAAAAAAA-TAAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over